TY - JOUR
T1 - Mutant FOXL2C134W hijacks SMAD4 and SMAD2/3 to drive adult granulosa cell tumors
AU - Weis-Banke, Stine E.
AU - Lerdrup, Mads
AU - Kleine-Kohlbrecher, Daniela
AU - Mohammad, Faizaan
AU - Sidoli, Simone
AU - Jensen, Ole N.
AU - Yanase, Toshihiko
AU - Nakamura, Tomoko
AU - Iwase, Akira
AU - Stylianou, Anthe
AU - Abu-Rustum, Nadeem R.
AU - Aghajanian, Carol
AU - Soslow, Robert
AU - da Cruz Paula, Arnaud
AU - Koche, Richard P.
AU - Weigelt, Britta
AU - Christensen, Jesper
AU - Helin, Kristian
AU - Cloos, Paul A.C.
N1 - Funding Information:
We thank Bente Møller and Ulla Toftega°rd for expert technical assistance, members of the Helin laboratory for discussions, and P. Selenica for sequence data handling. The work in the Helin laboratory was supported by the Danish Cancer Society (R167-A10877), the Danish National Research Foundation (DNRF82), the Independent Research Fund Denmark (6153-000005; 7016-00067; 8020-00044), The Neye Foundation, the Novo Nordisk Foundation (NNF; NNF16OC0023234), through a center grant from the NNF to the NNF Center for Stem Cell Biology (NNF17CC0027852) and through the Memorial Sloan Kettering Cancer Center Support Grant (NIH P30 CA008748). Proteomics research in the Jensen laboratory at SDU was supported by the Danish National Research Foundation (DNRF82), the
Funding Information:
We thank Bente Møller and Ulla Toftegard for expert technical assistance, members of the Helin laboratory for discussions, and P. Selenica for sequence data handling. The work in the Helin laboratory was supported by the Danish Cancer Society (R167-A10877), the Danish National Research Foundation (DNRF82), the Independent Research Fund Denmark (6153-000005; 7016-00067; 8020-00044), The Neye Foundation, the Novo Nordisk Foundation (NNF; NNF16OC0023234), through a center grant from the NNF to the NNF Center for Stem Cell Biology (NNF17CC0027852) and through the Memorial Sloan Kettering Cancer Center Support Grant (NIH P30 CA008748). Proteomics research in the Jensen laboratory at SDU was supported by the Danish National Research Foundation (DNRF82), the VILLUM Foundation (VILLUM Center for Bioanalytical Sciences, grant no. 7292), and PRO-MS: Danish National Mass Spectrometry Platform for Functional Proteomics (grant no. 5072-00007B). B. Weigelt was funded in part by Breast Cancer Research Foundation, Cycle for Survival, and Stand Up To Cancer-American Association for Cancer Research Dream Team Translational Cancer Research grant.
Funding Information:
N.R. Abu-Rustum reports grants from GRAIL and Stryker/Novadaq during the conduct of the study, and GRAIL and Stryker/Novadaq outside the submitted work. C. Aghajanian reports personal fees from Abbvie (one time advisory board, April 8, 2020), Clovis (one time advisory board, March 22, 2018), Eisai (Merck) (endometrial cancer strategic council, Decemeber 5, 2019), ImmunoGen, Inc (one time advisory board, March 23, 2018), Mersana (one time advisory board, November 7, 2019), Roche (one time advisory board, November 14, 2019), and Tesaro (one time advisory boards, January 24, 2018 and July 11, 2018), grants from AstraZeneca (D081RC00001/ENGOT-ov46/AGO-OVAR 23/GOG-3025: a phase III randomized, double-blind, placebo-controlled, multicenter study of durvalumab in combination with chemotherapy and bevacizumab, followed by maintenance durvalumab, bev-acizumab, and olaparib in newly diagnosed advanced ovarian cancer patients (role: national coordinating investigator and MSK principal investigator), Genentech (YO39523/GOG-3015: a phase III, multicenter, randomized study of atezolizumab versus placebo administered in combination with paclitaxel, carboplatin, and bev-acizumab to patients with newly diagnosed stage iii or stage iv ovarian, fallopian tube, or primary peritoneal cancer; steering committee member and MSK principal investigator), AbbVie [M13-694/GOG 3005: a phase III placebo-controlled study of carboplatin/paclitaxel with or without concurrent and continuation maintenance veliparib (parp inhibitor) in subjects with previously untreated stages III or IV high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer], Clovis (CO-338-014/ARIEL3 and CO-338-017/ARIEL2; role: MSK principal investigator), and AstraZeneca (SOLO1/GOG 3004; MSK principal investigator) outside the submitted work. R. Soslow reports grants from NIH during the conduct of the study, as well as personal fees from EBIX/Oakstone, Springer Publishing, and Cambridge University Press outside the submitted work. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
VILLUM Foundation (VILLUM Center for Bioanalytical Sciences, grant no. 7292), and PRO-MS: Danish National Mass Spectrometry Platform for Functional Proteomics (grant no. 5072-00007B). B. Weigelt was funded in part by Breast Cancer Research Foundation, Cycle for Survival, and Stand Up To Cancer-American Association for Cancer Research Dream Team Translational Cancer Research grant.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - The mutant protein FOXL2C134W is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2C134W contributes to tumorigenesis is not known. Here, we show that mutant FOXL2C134W acquires the ability to bind SMAD4, forming a FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2C134W mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2C134W also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2C134W binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGFb mitigated the transcriptional effect of FOXL2C134W. Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2C134W and its interaction with SMAD4 as potential therapeutic targets to this condition.
AB - The mutant protein FOXL2C134W is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2C134W contributes to tumorigenesis is not known. Here, we show that mutant FOXL2C134W acquires the ability to bind SMAD4, forming a FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2C134W mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2C134W also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2C134W binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGFb mitigated the transcriptional effect of FOXL2C134W. Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2C134W and its interaction with SMAD4 as potential therapeutic targets to this condition.
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U2 - 10.1158/0008-5472.CAN-20-0259
DO - 10.1158/0008-5472.CAN-20-0259
M3 - Article
C2 - 32641411
AN - SCOPUS:85099104308
SN - 0008-5472
VL - 80
SP - 3466
EP - 3479
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -
