TACC3

Gene Summary

Gene:TACC3; transforming acidic coiled-coil containing protein 3
Aliases: ERIC1, Tacc4, ERIC-1, maskin
Location:4p16.3
Summary:This gene encodes a member of the transforming acidic colied-coil protein family. The encoded protein is a motor spindle protein that may play a role in stabilization of the mitotic spindle. This protein may also play a role in growth a differentiation of certain cancer cells. [provided by RefSeq, Nov 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transforming acidic coiled-coil-containing protein 3
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: TACC3 (cancer-related)

Na K, Kim HS, Shim HS, et al.
Targeted next-generation sequencing panel (TruSight Tumor 170) in diffuse glioma: a single institutional experience of 135 cases.
J Neurooncol. 2019; 142(3):445-454 [PubMed] Related Publications
PURPOSE: The TruSight Tumor 170 (TST-170) panel consists of a DNA workflow for the identification of single-nucleotide variants, small insertions and deletions, and copy number variation, as well as a panel of 55 genes for a RNA workflow for the identification of splice variants and gene fusions. To date, the application of TST-170 in diffuse gliomas (DGs) has not been described.
METHODS: We analyzed 135 samples of DG, which were diagnosed by WHO criteria based on histological features and conventional molecular tests including immunostaining, 1p/19q FISH, and analysis of MGMT methylation and TERT promoter mutation.
RESULTS: A total of 135 cases consisted of 38 IDH-mutant [17 astrocytoma (AC), 13 oligodendroglioma (OD) and eight glioblastoma (GBM)], 87 IDH-wildtype (six AC, three OD and 78 GBM), and 10 diffuse midline glioma, H3K27M-mutant. DNA analysis enabled the detection of all mutations identified in these samples by conventional techniques, and the results were highly comparable to the known mutations in each subtype. RNA analysis detected four fusion genes including PTPRZ1-MET, FGFR3-TACC3, FAM131B-BRAF, and RET-CCDC6 and one splicing variant (EGFR vIII mutant). Clustered copy number loss in 1p and 19q loci genes were detected in 1p/19q-codeleted OD.
CONCLUSIONS: The application of TST-170 panel based NGS in clinical and laboratory setting is expected to improve diagnostic accuracy and prognostication. Most benefits are expected in IDH-wildtype DG, a group of genetically heterogenous tumors harboring DNA sequence changes, copy number alterations, and fusions in a large number of oncogenes and tumor suppressor genes.

Bellmunt J, Lalani AA, Jacobus S, et al.
Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma.
Br J Cancer. 2018; 119(6):707-712 [PubMed] Related Publications
BACKGROUND: Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC.
METHODS: mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods.
RESULTS: Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion.
CONCLUSIONS: Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.

Tan TZ, Rouanne M, Tan KT, et al.
Molecular Subtypes of Urothelial Bladder Cancer: Results from a Meta-cohort Analysis of 2411 Tumors.
Eur Urol. 2019; 75(3):423-432 [PubMed] Related Publications
BACKGROUND: Previous molecular subtyping for bladder carcinoma (BLCA) involved <450 samples, with diverse classifications.
OBJECTIVE: To identify molecular subtypes by curating a large BLCA dataset.
DESIGN, SETTING, AND PARTICIPANTS: Gene expression publicly available were combined and reanalyzed. The dataset contained 2411 unique tumors encompassing non-muscle-invasive (NMIBC) and muscle-invasive BLCA (MIBC). Subtypes were reproduced on The Cancer Genome Atlas, UROMOL, and IMvigor210.
INTERVENTION: Subtypes were assigned by gene expression.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier analyses were performed for subtype-clinical outcome correlations; Chi-square/Fisher exact tests were used for subtype-clinicopathological parameters associations.
RESULTS AND LIMITATIONS: We identified six molecular subtypes with different overall survival (OS) and molecular features. Subtype Neural-like (median OS, 87 mo) is prevalent in MIBC and characterized by high WNT/β-catenin signaling. HER2-like (107.7 mo) is distributed evenly across NMIBC and MIBC, with higher ERBB2 amplification and signaling. Papillary-like (>135 mo), an NMIBC subtype enriched in urothelial differentiation genes, shows a high frequency of actionable FGFR3 mutations, amplifications, and FGFR3-TACC3 fusion. Luminal-like (91.7 mo), predominantly NMIBC, has higher MAPK signaling and more KRAS and KMT2C/D mutations than other subtypes. Mesenchymal-like (MES; 86.6 mo) and Squamous-cell carcinoma-like (SCC; 20.6 mo) are predominant in MIBC. MES is high in AXL signaling, whereas SCC has elevated PD1, CTLA4 signaling, and macrophage M2 infiltration. About 20% of NMIBCs show MIBC subtype traits and a lower 5-yr OS rate than Papillary-like NMIBC (81% vs 96%). The main limitations of our study are the incomplete clinical annotation, and the analyses were based on transcriptome subset due to comparisons across gene expression quantification technologies.
CONCLUSIONS: BLCA can be stratified into six molecular subtypes. NMIBC, with a high risk of progression, displays the molecular features of MIBC.
PATIENT SUMMARY: Biomarkers are urgently needed to guide patient treatment selection and avoid unnecessary toxicities in those who fail to respond. We believe molecular subtyping is a promising way to tailor disease management for those who will benefit most.

Kim YS, Kim K, Kwon GY, et al.
Fibroblast growth factor receptor 3 (FGFR3) aberrations in muscle-invasive urothelial carcinoma.
BMC Urol. 2018; 18(1):68 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent studies suggest that FGFR3 is a potential therapeutic target in urothelial carcinoma (UC). The purpose of this study was to evaluate the rates and types of FGFR3 aberrations in patients with muscle-invasive UC who received radical resection.
METHODS: We analyzed surgical tumor samples from 74 UC patients who had received radical cystectomy (n = 40) or ureteronephrectomy (n = 34). Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay were used to detect FGFR3 aberrations.
RESULTS: Fifty-four patients (73%) had high-grade tumors, and 62% had lymph node involvement. Sixteen patients (22%) harbored FGFR3 alterations, the most common of which was FGFR3 mutations (n = 13): Y373C (n = 3), N532D (n = 3), R248C (n = 2), S249C (n = 1), G370C (n = 1), S657S (n = 1), A797P (n = 1), and 746_747insG (n = 1). Three additional patients had a FGFR3-TACC3 rearrangement. The frequency of FGFR3 aberrations was higher in bladder UC (25%) than in UC of the renal pelvis and ureter (18%) but the difference was not statistically significant (P = 0.444). Genes that were co-aberrant with FGFR3 included APC (88%), PDGFRA (81%), RET (69%), and TP53 (69%).
CONCLUSIONS: We report the frequency and types of FGFR3 aberrations in Korean patients with UC. Patients with FGFR3 mutations or FGFR3-TACC3 fusion may constitute potential candidates for a novel FGFR-targeted therapy in the perioperative setting.

Best SA, Harapas CR, Kersbergen A, et al.
FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium.
Oncogene. 2018; 37(46):6096-6104 [PubMed] Free Access to Full Article Related Publications
Structural rearrangements of the genome can drive lung tumorigenesis through the generation of fusion genes with oncogenic properties. Advanced genomic approaches have identified the presence of a genetic fusion between fibroblast growth factor receptor 3 (FGFR3) and transforming acidic coiled-coil 3 (TACC3) in non-small cell lung cancer (NSCLC), providing a novel target for FGFR inhibition. To interrogate the functional consequences of the FGFR3-TACC3 fusion in the transformation of lung epithelial cells, we generated a novel transgenic mouse model that expresses FGFR3-TACC3 concomitant with loss of the p53 tumor suppressor gene. Intranasal delivery of an Ad5-CMV-Cre virus promoted seromucinous glandular transformation of olfactory cells lining the nasal cavities of FGFR3-TACC3 (LSL-F3T3) mice, which was further accelerated upon loss of p53 (LSL-F3T3/p53). Surprisingly, lung tumors failed to develop in intranasally infected LSL-F3T3 and LSL-F3T3/p53 mice. In line with these observations, we demonstrated that intranasal delivery of Ad5-CMV-Cre induces widespread Cre-mediated recombination in the olfactory epithelium. Intra-tracheal delivery of Ad5-CMV-Cre into the lungs of LSL-F3T3 and LSL-F3T3/p53 mice, however, resulted in the development of lung adenocarcinomas. Taken together, these findings provide in vivo evidence for an oncogenic function of FGFR3-TACC3 in respiratory epithelium.

Wang Y, Ding X, Hu H, et al.
Long non-coding RNA lnc-PCTST predicts prognosis through inhibiting progression of pancreatic cancer by downregulation of TACC-3.
Int J Cancer. 2018; 143(12):3143-3154 [PubMed] Related Publications
Pancreatic cancer (PC), which is one of the most lethal of malignancies and a major health burden, is associated with a dismal prognosis despite current therapeutic advances. Numerous long noncoding RNAs (lncRNA) have shown to be essential for PC tumorigenesis and progression. Nevertheless, the exact expression pattern of lnc-PCTST and its clinical significance still remain unclear. This study investigates the expression pattern of lnc-PCTST and its associated mRNA in three paired PC tissues and adjacent non-tumor tissues by Microarray-coarray approach. Briefly, our data demonstrated that lnc-PCTST expression is down-regulated in PC tissues. Also, lnc-PCTST has shown to be negatively correlated with transforming acidic coiled-coil 3 (TACC-3) expression. This expression pattern was further confirmed following qRT-PCR validation of 34 out of 48 paired cancer tissues. Furthermore, lnc-PCTST overexpression in PC cell lines inhibited cell proliferation and invasion in vitro, and tumorigenesis in vivo (using nude mice as animal model), but did not altered cell migration. Moreover, lnc-PCTST overexpression increased E-cadherin and repressed vimentin expression in vitro. Additionally, TACC-3 knockdown simulated the inhibiting effect of lnc-PCTST overexpression on PC cell lines, and the impaired proliferation, invasion effect and E-cadherin, vimentin expression on lnc-PCTST over-expressed cell lines can be rescued by overexpressed TACC-3. Significantly, the expression of lnc-PCTST was closely associated with its genomic neighboring gene TACC-3 and inhibited its promoter activity. In conclusion, lnc-PCTST is a potential tumor suppressor in PC, which inhibits cell proliferation, invasion, tumorigenesis and EMT by modulating TACC-3.

Dhami J, Hirshfield KM, Ganesan S, et al.
Comprehensive genomic profiling aids in treatment of a metastatic endometrial cancer.
Cold Spring Harb Mol Case Stud. 2018; 4(2) [PubMed] Free Access to Full Article Related Publications

Campo L, Breuer EK
Inhibition of TACC3 by a small molecule inhibitor in breast cancer.
Biochem Biophys Res Commun. 2018; 498(4):1085-1092 [PubMed] Related Publications
Studies have shown that transforming acidic coiled-coil protein 3 (TACC3), a key component of centrosome-microtubule dynamic networks, is significantly associated with various types of human cancer. We have recently reported that high levels of TACC3 are found in breast cancer, lead to the accumulation of spontaneous DNA damage due to defective DNA damage response signaling, and confer cellular sensitivity to radiation and poly(ADP-ribose) polymerase (PARP) inhibitors. Although our study suggests a potential role of TACC3 as a biomarker in breast cancer detection and prediction of therapy outcome, its role as a therapeutic target in breast cancer is not well studied. In this study, we show that a small molecule TACC3 inhibitor, KHS101, suppresses cell growth, motility, epithelial-mesenchymal transition (EMT), and breast cancer cell stemness while it induces apoptotic cell death. Quantitative multiplexed proteomic analysis using tandem mass tags (TMTs) revealed that KHS101 alters multiple biological processes and signaling pathways, and significantly reduces the expression of mitotic kinases Aurora A and Polo-like kinase 1 (PLK1), which are closely associated with TACC3. Our findings therefore provide a new insight into the potential mechanisms of the action of KHS101 and suggest its possible use as a dual or multi-targeting mitotic inhibitor in breast cancer.

Mall R, Cerulo L, Garofano L, et al.
RGBM: regularized gradient boosting machines for identification of the transcriptional regulators of discrete glioma subtypes.
Nucleic Acids Res. 2018; 46(7):e39 [PubMed] Free Access to Full Article Related Publications
We propose a generic framework for gene regulatory network (GRN) inference approached as a feature selection problem. GRNs obtained using Machine Learning techniques are often dense, whereas real GRNs are rather sparse. We use a Tikonov regularization inspired optimal L-curve criterion that utilizes the edge weight distribution for a given target gene to determine the optimal set of TFs associated with it. Our proposed framework allows to incorporate a mechanistic active biding network based on cis-regulatory motif analysis. We evaluate our regularization framework in conjunction with two non-linear ML techniques, namely gradient boosting machines (GBM) and random-forests (GENIE), resulting in a regularized feature selection based method specifically called RGBM and RGENIE respectively. RGBM has been used to identify the main transcription factors that are causally involved as master regulators of the gene expression signature activated in the FGFR3-TACC3-positive glioblastoma. Here, we illustrate that RGBM identifies the main regulators of the molecular subtypes of brain tumors. Our analysis reveals the identity and corresponding biological activities of the master regulators characterizing the difference between G-CIMP-high and G-CIMP-low subtypes and between PA-like and LGm6-GBM, thus providing a clue to the yet undetermined nature of the transcriptional events among these subtypes.

Lin ZR, Wang MY, He SY, et al.
TACC3 transcriptionally upregulates E2F1 to promote cell growth and confer sensitivity to cisplatin in bladder cancer.
Cell Death Dis. 2018; 9(2):72 [PubMed] Free Access to Full Article Related Publications
Accumulating evidence has shown that transforming acidic coiled-coil 3 (TACC3) is deregulated in a broad spectrum of cancers. In the present study, we reported that TACC3 was markedly elevated in bladder cancer, especially in muscle-invasive bladder cancers (MIBCs). The upregulation of TACC3 was positively associated with tumor invasiveness, grade, T stage, and progression in patients with bladder cancer. Furthermore, a Kaplan-Meier survival analysis showed that patients with bladder cancer whose tumors had high TACC3 expression experienced a dismal prognosis compared with patients whose tumors had low TACC3 expression. Functional studies have found that TACC3 is a prerequisite for the development of malignant characteristics of bladder cancer cells, including cell proliferation and invasion. Moreover, TACC3 promoted G1/S transition, which was mediated via activation of the transcription of E2F1, eventually enhancing cell proliferation. Notably, the overexpression of TACC3 or E2F1 indicates a high sensitivity to cisplatin. Taken together, these findings define a tumor-supportive role for TACC3, which may also serve as a prognostic and therapeutic indicator in bladder cancers.

Kim JL, Ha GH, Campo L, Breuer EK
Negative regulation of BRCA1 by transforming acidic coiled-coil protein 3 (TACC3).
Biochem Biophys Res Commun. 2018; 496(2):633-640 [PubMed] Related Publications
In spite of the push to identify modifiers of BRCAness, it still remains unclear how tumor suppressor BRCA1 is lost in breast cancers in the absence of genetic or epigenetic aberrations. Mounting evidence indicates that the transforming acidic coiled-coil 3 (TACC3) plays an important role in the centrosome-microtubule network during mitosis and gene expression, and that deregulation of TACC3 is associated with breast cancer. However, the molecular mechanisms by which TACC3 contributes to breast cancer development have yet to be elucidated. Herein, we found that high levels of TACC3 in human mammary epithelial cells can cause genomic instability possibly in part through destabilizing BRCA1. We also found that high levels of TACC3 inhibited the interaction between BRCA1 and BARD1, thus subsequently allowing the BARD1-uncoupled BRCA1 to be destabilized by ubiquitin-mediated proteosomal pathway. Moreover, there is an inverse correlation between TACC3 and BRCA1 expression in breast cancer tissues. Overall, our findings provide a new insight into the role of TACC3 in genomic instability and breast tumorigenesis.


FGFR3-TACC3 Activates Mitochondrial Respiration via PIN4 Phosphorylation.
Cancer Discov. 2018; 8(2):139 [PubMed] Related Publications
PIN4 is a FGFR3-TACC3 substrate required for ROS-mediated induction of PGCIα and tumor growth.

Frattini V, Pagnotta SM, Tala, et al.
A metabolic function of FGFR3-TACC3 gene fusions in cancer.
Nature. 2018; 553(7687):222-227 [PubMed] Free Access to Full Article Related Publications
Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies. We have previously described gene fusions of FGFR3-TACC3 (F3-T3) in 3% of human glioblastoma cases. Subsequent studies have reported similar frequencies of F3-T3 in many other cancers, indicating that F3-T3 is a commonly occuring fusion across all tumour types. F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown. Here we show that human tumours with F3-T3 fusions cluster within transcriptional subgroups that are characterized by the activation of mitochondrial functions. F3-T3 activates oxidative phosphorylation and mitochondrial biogenesis and induces sensitivity to inhibitors of oxidative metabolism. Phosphorylation of the phosphopeptide PIN4 is an intermediate step in the signalling pathway of the activation of mitochondrial metabolism. The F3-T3-PIN4 axis triggers the biogenesis of peroxisomes and the synthesis of new proteins. The anabolic response converges on the PGC1α coactivator through the production of intracellular reactive oxygen species, which enables mitochondrial respiration and tumour growth. These data illustrate the oncogenic circuit engaged by F3-T3 and show that F3-T3-positive tumours rely on mitochondrial respiration, highlighting this pathway as a therapeutic opportunity for the treatment of tumours with F3-T3 fusions. We also provide insights into the genetic alterations that initiate the chain of metabolic responses that drive mitochondrial metabolism in cancer.

Bielle F, Di Stefano AL, Meyronet D, et al.
Diffuse gliomas with FGFR3-TACC3 fusion have characteristic histopathological and molecular features.
Brain Pathol. 2018; 28(5):674-683 [PubMed] Related Publications
Adult glioblastomas, IDH-wildtype represent a heterogeneous group of diseases. They are resistant to conventional treatment by concomitant radiochemotherapy and carry a dismal prognosis. The discovery of oncogenic gene fusions in these tumors has led to prospective targeted treatments, but identification of these rare alterations in practice is challenging. Here, we report a series of 30 adult diffuse gliomas with an in frame FGFR3-TACC3 oncogenic fusion (n = 27 WHO grade IV and n = 3 WHO grade II) as well as their histological and molecular features. We observed recurrent morphological features (monomorphous ovoid nuclei, nuclear palisading and thin parallel cytoplasmic processes, endocrinoid network of thin capillaries) associated with frequent microcalcifications and desmoplasia. We report a constant immunoreactivity for FGFR3, which is a valuable method for screening for the FGFR3-TACC3 fusion with 100% sensitivity and 92% specificity. We confirmed the associated molecular features (typical genetic alterations of glioblastoma, except the absence of EGFR amplification, and an increased frequency of CDK4 and MDM2 amplifications). FGFR3 immunopositivity is a valuable tool to identify gliomas that are likely to harbor the FGFR3-TACC3 fusion for inclusion in targeted therapeutic trials.

Johnson A, Severson E, Gay L, et al.
Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.
Oncologist. 2017; 22(12):1478-1490 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making.
MATERIALS AND METHODS: We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]).
RESULTS: In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors.
CONCLUSION: Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy.
IMPLICATIONS FOR PRACTICE: By providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for advancing care for pediatric neuro-oncology patients. This article presents the largest cohort of pediatric low- and high-grade gliomas profiled by next-generation sequencing. Reportable alterations were detected in 95% of patients, including diagnostically relevant lesions as well as novel oncogenic fusions and mutations. Additionally, tumor mutational burden (TMB) is reported, which identifies a subpopulation of hypermutated glioblastomas that harbor deleterious mutations in DNA repair genes. This provides support for TMB as a potential biomarker to identify patients who may preferentially benefit from immune checkpoint inhibitors.

Sarkar S, Ryan EL, Royle SJ
FGFR3-TACC3 cancer gene fusions cause mitotic defects by removal of endogenous TACC3 from the mitotic spindle.
Open Biol. 2017; 7(8) [PubMed] Free Access to Full Article Related Publications
Fibroblast growth factor receptor 3-transforming acidic coiled-coil containing protein 3 (FGFR3-TACC3; FT3) is a gene fusion resulting from rearrangement of chromosome 4 that has been identified in many cancers including those of the urinary bladder. Altered FGFR3 signalling in FT3-positive cells is thought to contribute to cancer progression. However, potential changes in TACC3 function in these cells have not been explored. TACC3 is a mitotic spindle protein required for accurate chromosome segregation. Errors in segregation lead to aneuploidy, which can contribute to cancer progression. Here we show that FT3-positive bladder cancer cells have lower levels of endogenous TACC3 on the mitotic spindle, and that this is sufficient to cause mitotic defects. FT3 is not localized to the mitotic spindle, and by virtue of its TACC domain, recruits endogenous TACC3 away from the spindle. Knockdown of the fusion gene or low-level overexpression of TACC3 partially rescues the chromosome segregation defects in FT3-positive bladder cancer cells. This function of FT3 is specific to TACC3 as inhibition of FGFR3 signalling does not rescue the TACC3 level on the spindle in these cancer cells. Models of FT3-mediated carcinogenesis should, therefore, include altered mitotic functions of TACC3 as well as altered FGFR3 signalling.

Granberg KJ, Annala M, Lehtinen B, et al.
Strong FGFR3 staining is a marker for FGFR3 fusions in diffuse gliomas.
Neuro Oncol. 2017; 19(9):1206-1216 [PubMed] Free Access to Full Article Related Publications
Background: Inhibitors of fibroblast growth factor receptors (FGFRs) have recently arisen as a promising treatment option for patients with FGFR alterations. Gene fusions involving FGFR3 and transforming acidic coiled-coil protein 3 (TACC3) have been detected in diffuse gliomas and other malignancies, and fusion-positive cases have responded well to FGFR inhibition. As high FGFR3 expression has been detected in fusion-positive tumors, we sought to determine the clinical significance of FGFR3 protein expression level as well as its potential for indicating FGFR3 fusions.
Methods: We performed FGFR3 immunohistochemistry on tissue microarrays containing 676 grades II-IV astrocytomas and 116 grades II-III oligodendroglial tumor specimens. Fifty-one cases were further analyzed using targeted sequencing.
Results: Moderate to strong FGFR3 staining was detected in gliomas of all grades, was more common in females, and was associated with poor survival in diffuse astrocytomas. Targeted sequencing identified FGFR3-TACC3 fusions and an FGFR3-CAMK2A fusion in 10 of 15 strongly stained cases, whereas no fusions were found in 36 negatively to moderately stained cases. Fusion-positive cases were predominantly female and negative for IDH and EGFR/PDGFRA/MET alterations. These and moderately stained cases show lower MIB-1 proliferation index than negatively to weakly stained cases. Furthermore, stronger FGFR3 expression was commonly observed in malignant tissue regions of lower cellularity in fusion-negative cases. Importantly, subregional negative FGFR3 staining was also observed in a few fusion-positive cases.
Conclusions: Strong FGFR3 protein expression is indicative of FGFR3 fusions and may serve as a clinically applicable predictive marker for treatment regimens based on FGFR inhibitors.

Sun Y, Tian Y, Wang GZ, et al.
Overexpression of Transforming Acidic Coiled Coil‑Containing Protein 3 Reflects Malignant Characteristics and Poor Prognosis of Glioma.
Int J Mol Sci. 2017; 18(3) [PubMed] Free Access to Full Article Related Publications
Gliomas are malignant primary brain tumors with poor prognosis. Recently, research was indicative of a tight connection between tumor malignancy and genetic alterations. Here, we propose an oncogenic implication of transforming acidic coiled-coil-containing protein 3 (TACC3) in gliomas. By comprehensively analyzing the Chinese glioma genome atlas (CGGA) and publicly available data, we demonstrated that TACC3 were overexpressed along with glioma grade and served as an independent negative prognostic biomarker for glioma patients. Functions' annotations and gene sets' enrichment analysis suggested that TACC3 may participate in cell cycle, DNA repair, epithelium-mesenchymal transition and other tumor-related biological processes and molecular pathways. Patients with high TACC3 expression showed CD133⁺ stem cell properties, glioma plasticity and shorter overall survival time under chemo-/radio-therapy. Additionally, a TACC3 associated the miRNA-mRNA network was constructed based on in silico prediction and expression pattern, which provide a foundation for further detection of TACC3-miRNA-mRNA axis function. Collectively, our observations identify TACC3 as an oncogene of tumor malignancy, as well as a prognostic and motoring biomarker for glioma patients.

Nozad S, Sheehan CE, Gay LM, et al.
Comprehensive genomic profiling of malignant phyllodes tumors of the breast.
Breast Cancer Res Treat. 2017; 162(3):597-602 [PubMed] Related Publications
PURPOSE: Malignant phyllodes tumors (MPT) are exceptionally rare, and the genomic drivers of these tumors are still being elucidated. We performed comprehensive genomic profiling (CGP) of MPT to identify genomic alterations that will inform approaches to targeted therapy for patients with MPT, including relapsed, refractory, and metastatic disease.
METHODS: DNA was extracted from formalin-fixed, paraffin-embedded samples from 24 consecutive patient cases of MPT. CGP was performed using a hybrid capture, adaptor ligation-based next generation sequencing assay to a high, uniform coverage (mean, 582×). Tumor mutational burden (TMB) was calculated from a minimum of 1.14 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations, including short variants (SV; base substitutions, small insertions, and deletions), rearrangements, and copy number changes, including amplifications and homozygous deletions.
RESULTS: The 24 cases of MPT included 15 patients with localized and 9 with metastatic disease. The median TMB was 2.7 mut/Mb, and no cases had a TMB > 10 mut/Mb. 20 out of 24 cases were evaluable for microsatellite status, and all were microsatellite stable. The most commonly mutated genes were TP53 (58.3%), TERT-promoter (57.9%), NF1 (45.8%), MED12 (45.8%), CDKN2A/B (33.3%), and MLL2 (33.3%). Targetable kinase fusions including KIAA1549-BRAF or FGFR3-TACC3 were identified in 2/24 (8.3%) tumors.
CONCLUSIONS: This study identifies clinically relevant genomic alterations that suggest novel targeted therapy approaches for patients with MPT.

Guo F, Liu Y
Knockdown of TACC3 Inhibits the Proliferation and Invasion of Human Renal Cell Carcinoma Cells.
Oncol Res. 2018; 26(2):183-189 [PubMed] Related Publications
Transforming acidic coiled-coil protein 3 (TACC3) is a member of the TACC family and plays an important role in regulating cell mitosis, transcription, and tumorigenesis. However, the expression pattern and roles of TACC3 in renal cell carcinoma (RCC) remain unclear. The aim of this study was to investigate the role of TACC3 in RCC. We demonstrated overexpression of TACC3 in human RCC cell lines at both RNA and protein levels. Moreover, knockdown of TACC3 repressed RCC cell proliferation, migration, and invasion in vitro. In addition, knockdown of TACC3 inactivated PI3K/Akt signaling in RCC cells. Furthermore, knockdown of TACC3 significantly reduced tumor growth in xenograft tumor-bearing mice. Taken together, our findings showed that TACC3 was increased in human RCC cell lines, and knockdown of TACC3 inhibited the ability of cell proliferation, migration, invasion, and tumorigenesis in vivo. Therefore, TACC3 may act as a therapeutic target for the treatment of human RCC.

Wang L, Šuštić T, Leite de Oliveira R, et al.
A Functional Genetic Screen Identifies the Phosphoinositide 3-kinase Pathway as a Determinant of Resistance to Fibroblast Growth Factor Receptor Inhibitors in FGFR Mutant Urothelial Cell Carcinoma.
Eur Urol. 2017; 71(6):858-862 [PubMed] Related Publications
Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation). We identified multiple members of the phosphoinositide 3-kinase (PI3K) pathway and found that inhibition of PIK3CA acts synergistically with FGFR inhibitors. The PI3K inhibitor BKM120 acted synergistically with inhibition of FGFR in multiple UCC and lung cancer cell lines having FGFR mutations. Consistently, we observed an elevated PI3K-protein kinase B pathway activity resulting from epidermal growth factor receptor or Erb-B2 receptor tyrosine kinase 3 reactivation caused by FGFR inhibition as the underlying molecular mechanism of the synergy. Our data show that feedback pathways activated by FGFR inhibition converge on the PI3K pathway. These findings provide a strong rationale to test FGFR inhibitors in combination with PI3K inhibitors in cancers harboring genetic activation of FGFR genes.

Petschnigg J, Kotlyar M, Blair L, et al.
Systematic Identification of Oncogenic EGFR Interaction Partners.
J Mol Biol. 2017; 429(2):280-294 [PubMed] Free Access to Full Article Related Publications
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) that-once activated upon ligand binding-leads to receptor dimerization, recruitment of protein complexes, and activation of multiple signaling cascades. The EGFR is frequently overexpressed or mutated in various cancers leading to aberrant signaling and tumor growth. Hence, identification of interaction partners that bind to mutated EGFR can help identify novel targets for drug discovery. Here, we used a systematic approach to identify novel proteins that are involved in cancerous EGFR signaling. Using a combination of high-content imaging and a mammalian membrane two-hybrid protein-protein interaction method, we identified eight novel interaction partners of EGFR, of which half strongly interacted with oncogenic, hyperactive EGFR variants. One of these, transforming acidic coiled-coil proteins (TACC) 3, stabilizes EGFR on the cell surface, which results in an increase in downstream signaling via the mitogen-activated protein kinase and AKT pathway. Depletion of TACC3 from cells using small hairpin RNA (shRNA) knockdown or small-molecule targeting reduced mitogenic signaling in non-small cell lung cancer cell lines, suggesting that targeting TACC3 has potential as a new therapeutic approach for non-small cell lung cancer.

Kurobe M, Kojima T, Nishimura K, et al.
Development of RNA-FISH Assay for Detection of Oncogenic FGFR3-TACC3 Fusion Genes in FFPE Samples.
PLoS One. 2016; 11(12):e0165109 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION AND OBJECTIVES: Oncogenic FGFR3-TACC3 fusions and FGFR3 mutations are target candidates for small molecule inhibitors in bladder cancer (BC). Because FGFR3 and TACC3 genes are located very closely on chromosome 4p16.3, detection of the fusion by DNA-FISH (fluorescent in situ hybridization) is not a feasible option. In this study, we developed a novel RNA-FISH assay using branched DNA probe to detect FGFR3-TACC3 fusions in formaldehyde-fixed paraffin-embedded (FFPE) human BC samples.
MATERIALS AND METHODS: The RNA-FISH assay was developed and validated using a mouse xenograft model with human BC cell lines. Next, we assessed the consistency of the RNA-FISH assay using 104 human BC samples. In this study, primary BC tissues were stored as frozen and FFPE tissues. FGFR3-TACC3 fusions were independently detected in FFPE sections by the RNA-FISH assay and in frozen tissues by RT-PCR. We also analyzed the presence of FGFR3 mutations by targeted sequencing of genomic DNA extracted from deparaffinized FFPE sections.
RESULTS: FGFR3-TACC3 fusion transcripts were identified by RNA-FISH and RT-PCR in mouse xenograft FFPE tissues using the human BC cell lines RT112 and RT4. These cell lines have been reported to be fusion-positive. Signals for FGFR3-TACC3 fusions by RNA-FISH were positive in 2/60 (3%) of non-muscle-invasive BC (NMIBC) and 2/44 (5%) muscle-invasive BC (MIBC) patients. The results of RT-PCR of all 104 patients were identical to those of RNA-FISH. FGFR3 mutations were detected in 27/60 (45%) NMIBC and 8/44 (18%) MIBC patients. Except for one NMIBC patient, FGFR3 mutation and FGFR3-TACC3 fusion were mutually exclusive.
CONCLUSIONS: We developed an RNA-FISH assay for detection of the FGFR3-TACC3 fusion in FFPE samples of human BC tissues. Screening for not only FGFR3 mutations, but also for FGFR3-TACC3 fusion transcripts has the potential to identify additional patients that can be treated with FGFR inhibitors.

Wang Z, Zhang C, Sun L, et al.
FGFR3, as a receptor tyrosine kinase, is associated with differentiated biological functions and improved survival of glioma patients.
Oncotarget. 2016; 7(51):84587-84593 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Activation of receptor tyrosine kinases is common in Malignancies. FGFR3 fusion with TACC3 has been reported to have transforming effects in primary glioblastoma and display oncogenic activity in vitro and in vivo. We set out to investigate the role of FGFR3 in glioma through transcriptomic analysis.
RESULTS: FGFR3 increased in Classical subtype and Neural subtype consistently in CGGA and TCGA cohort. Similar patterns of FGFR3 distribution through subtypes were observed in CGGA and TCGA samples. Gene ontology analysis was performed with genes that were significantly correlated with FGFR3 expression. We found that positively associated biological processes of FGFR3 were focused on differentiated cellular functions and neuronal activities, while negatively correlated biological processes focused on mitosis and cell cycle phase. Clinical investigation showed that higher FGFR3 expression predicted improved survival for glioma patients, especially in Proneural subtype. Moreover, FGFR3 showed very limited relevance with other receptor tyrosine kinases in glioma at transcriptome level.
MATERIALS AND METHODS: FGFR3 expression data of glioma was obtained from Chinese Glioma Genome Atlas (CGGA) and TCGA (The Cancer Genome Atlas). In total, RNA sequencing data of 325 glioma samples and mRNA microarray data of 301 samples from CGGA dataset were enrolled into this study. To consolidate the findings that we have revealed in CGGA dataset, RNA-seq data of 672 glioma samples from TCGA dataset were used as a validation cohort. R language was used as the main tool to perform statistical analysis and graphical work.
CONCLUSIONS: FGFR3 expression increased in classical and neural subtypes and was associated with differentiated cellular functions. FGFR3 showed very limited correlation with other common receptor tyrosine kinases, and predicted improved survival for glioma patients.

He JC, Yao W, Wang JM, et al.
TACC3 overexpression in cholangiocarcinoma correlates with poor prognosis and is a potential anti-cancer molecular drug target for HDAC inhibitors.
Oncotarget. 2016; 7(46):75441-75456 [PubMed] Free Access to Full Article Related Publications
Histone deacetylases (HDACs) have been implicated in multiple malignant tumors, and HDAC inhibitors (HDACIs) exert anti-cancer effects. However, the expression of HDACs and the anti-tumor mechanism of HDACIs in cholangiocarcinoma (CCA) have not yet been elucidated. In this study, we found that expression of HDACs 2, 3, and 8 were up-regulated in CCA tissues and those patients with high expression of HDAC2 and/or HDAC3 had a worse prognosis. In CCA cells, two HDACIs, trichostatin (TSA) and vorinostat (SAHA), suppressed proliferation and induced apoptosis and G2/M cycle arrest. Microarray analysis revealed that TACC3 mRNA was down-regulated in CCA cells treated with TSA. TACC3 was highly expressed in CCA tissues and predicted a poor prognosis in CCA patients. TACC3 knockdown induced G2/M cycle arrest and suppressed the invasion, metastasis, and proliferation of CCA cells, both in vitro and in vivo. TACC3 overexpression reversed the effects of its knockdown. These findings suggest TACC3 may be a useful prognostic biomarker for CCA and is a potential therapeutic target for HDACIs.

Costa R, Carneiro BA, Taxter T, et al.
FGFR3-TACC3 fusion in solid tumors: mini review.
Oncotarget. 2016; 7(34):55924-55938 [PubMed] Free Access to Full Article Related Publications
Fibroblast growth factor receptors (FGFR) are transmembrane kinase proteins with growing importance in cancer biology given the frequency of molecular alterations and vast interface with multiple other signaling pathways. Furthermore, numerous FGFR inhibitors in clinical development demonstrate the expanding therapeutic relevance of this pathway. Indeed, results from early phase clinical trials already indicate that a subset of patients with advanced tumors derive benefit from FGFR targeted therapies. FGFR gene aberrations and FGFR gene rearrangements are relatively rare in solid malignancies. The recently described FGFR3-TACC3 fusion protein has a constitutively active tyrosine kinase domain and promotes aneuploidy. We summarize the prevalence data on FGFR3-TACC3 fusions among different histological tumor types and the preliminary evidence that this rearrangement represents a targetable molecular aberration in some patients with solid tumors.

Daly C, Castanaro C, Zhang W, et al.
FGFR3-TACC3 fusion proteins act as naturally occurring drivers of tumor resistance by functionally substituting for EGFR/ERK signaling.
Oncogene. 2017; 36(4):471-481 [PubMed] Free Access to Full Article Related Publications
The epidermal growth factor receptor (EGFR) is a clinically validated target in head and neck squamous cell carcinoma (HNSCC), where EGFR-blocking antibodies are approved for first-line treatment. However, as with other targeted therapies, intrinsic/acquired resistance mechanisms limit efficacy. In the FaDu HNSCC xenograft model, we show that combined blockade of EGFR and ERBB3 promotes rapid tumor regression, followed by the eventual outgrowth of resistant cells. RNA sequencing revealed that resistant cells express FGFR3-TACC3 fusion proteins, which were validated as drivers of the resistant phenotype by several approaches, including CRISPR-mediated inactivation of FGFR3-TACC3 fusion genes. Interestingly, analysis of signaling in resistant cell lines demonstrated that FGFR3-TACC3 fusion proteins promote resistance by preferentially substituting for EGFR/RAS/ERK signaling rather than ERBB3/PI3K/AKT signaling. Furthermore, although FGFR3-TACC3 fusion proteins promote resistance of additional EGFR-dependent HNSCC and lung cancer cell lines to EGFR blockade, they are unable to compensate for inhibition of PI3K signaling in PIK3CA-mutant HNSCC cell lines. Validation of FGFR3-TACC3 fusion proteins as endogenous drivers of resistance in our screen provides strong evidence that these fusions are capable of substituting for EGFR signaling. Thus, FGFR3-TACC3 fusion proteins may represent a novel mechanism of acquired resistance in EGFR-dependent cancers of multiple cell lineages.

Kartha N, Shen L, Maskin C, et al.
The Chromatin Remodeling Component Arid1a Is a Suppressor of Spontaneous Mammary Tumors in Mice.
Genetics. 2016; 203(4):1601-11 [PubMed] Free Access to Full Article Related Publications
Human cancer genome studies have identified the SWI/SNF chromatin remodeling complex member ARID1A as one of the most frequently altered genes in several tumor types. Its role as an ovarian tumor suppressor has been supported in compound knockout mice. Here, we provide genetic and functional evidence that Arid1a is a bona fide mammary tumor suppressor, using the Chromosome aberrations occurring spontaneously 3 (Chaos3) mouse model of sporadic breast cancer. About 70% of mammary tumors that formed in these mice contained a spontaneous deletion removing all or part of one Arid1a allele. Restoration of Arid1a expression in a Chaos3 mammary tumor line with low Arid1a levels greatly impaired its ability to form tumors following injection into cleared mammary glands, indicating that ARID1A insufficiency is crucial for maintenance of these Trp53-proficient tumors. Transcriptome analysis of tumor cells before and after reintroduction of Arid1a expression revealed alterations in growth signaling and cell-cycle checkpoint pathways, in particular the activation of the TRP53 pathway. Consistent with the latter, Arid1a reexpression in tumor cells led to increased p21 (Cdkn1a) expression and dramatic accumulation of cells in G2 phase of the cell cycle. These results not only provide in vivo evidence for a tumor suppressive and/or maintenance role in breast cancer, but also indicate a potential opportunity for therapeutic intervention in ARID1A-deficient human breast cancer subtypes that retain one intact copy of the gene and also maintain wild-type TRP53 activity.

Song H, Liu C, Shen N, et al.
Overexpression of TACC3 in Breast Cancer Associates With Poor Prognosis.
Appl Immunohistochem Mol Morphol. 2018; 26(2):113-119 [PubMed] Related Publications
Increasing evidences suggest that transforming acidic coiled-coil protein 3 (TACC3) is associated with various types of human cancer. However, the expression of TACC3 in breast cancer tissues remains largely unknown. To identify whether TACC3 can serve as a biomarker for the diagnosis and prognosis of breast cancer, quantitative polymerase chain reaction, western blotting, and immunohistochemistry staining were utilized to detect the expression of TACC3. The mRNA and protein levels of TACC3 in breast cancer samples were novelty higher compared with nontumorous breast tissues. Immunohistochemistry results revealed TACC3 expression was significantly correlated to lymphoid nodal metastasis (P=0.035) and HER-2 status (P=0.021). The patients with high expression of TACC3 had a significantly poor prognosis compared with patients with low expression (P=0.017), especially in the patients with pathological tumor size 2-4 status (P=0.028). Furthermore, multivariate analysis indicated that TACC3 expression was an independent prognostic factor for breast cancer patients (P=0.029). This study, first, suggested TACC3 might be an important molecular marker for diagnosis and prognosis of breast cancer.

Du Y, Liu L, Wang C, et al.
TACC3 promotes colorectal cancer tumourigenesis and correlates with poor prognosis.
Oncotarget. 2016; 7(27):41885-41897 [PubMed] Free Access to Full Article Related Publications
Colorectal carcinoma (CRC) is a malignant epithelial tumour with tremendous invasion and metastatic capacity. Transforming acidic coiled-coil protein-3 (TACC3), a frequently aberrantly expressed oncogene, is an important biomarker in various human cancers. Our study aimed to investigate the expression and function of TACC3 in human CRC. We found that TACC3 was over-expressed at both the mRNA and protein levels in CRC cells and in biopsies of CRC tissues compared with normal controls as determined by qRT-PCR, western blot and immunohistochemical (IHC) staining assays. IHC staining of samples from 161 patients with CRC also revealed that TACC3 expression was significantly correlated with clinical stage (P = 0.045), T classification (P = 0.029) and M classification (P = 0.020). Multivariate analysis indicated that high TACC3 expression was an independent prognostic marker for CRC. Patients who had high TACC3 expression had significantly poorer overall survival (OS, P = 0.023) and disease-free survival (DFS, P = 0.019) compared to patients who had low TACC3 expression. Furthermore, TACC3 knockdown attenuated CRC cell proliferation, colony formation capability, migration and invasion capability, and tumourigenesis in nude mice; these properties were measured using a real-time cell analyser (RTCA), clonogenicity analysis, and transwell and xenograft assays, respectively. These data indicate that TACC3 promotes CRC progression and could be an independent prognostic factor and a potential therapeutic target for CRC.

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