Mutant SF3B1 Promotes Malignancy in PDAC

Overview

Journal Elife

Specialty Biology

Date 2023 Oct 12

PMID 37823551

Authors

Patrik Simmler

Eleonora I Ioannidi

Tamara Mengis

Kim Fabiano Marquart

Simran Asawa

Kjong Van-Lehmann

Andre Kahles

Tinu Thomas

Cornelia Schwerdel

Nicola Aceto

Gunnar Ratsch

Markus Stoffel

Gerald Schwank

Affiliations

Soon will be listed here.

Abstract

The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1 on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1 alone is insufficient to induce malignant transformation of the murine pancreas, but that it increases aggressiveness of PDAC if it co-occurs with mutated KRAS and p53. We further show that Sf3b1 already plays a role during early stages of pancreatic tumor progression and reduces the expression of TGF-β1-responsive epithelial-mesenchymal transition (EMT) genes. Moreover, we found that SF3B1 confers resistance to TGF-β1-induced cell death in pancreatic organoids and cell lines, partly mediated through aberrant splicing of . Overall, our findings demonstrate that SF3B1 acts as an oncogenic driver in PDAC, and suggest that it promotes the progression of early stage tumors by impeding the cellular response to tumor suppressive effects of TGF-β.

Citing Articles

SUGP1 loss is the sole driver of SF3B1 hotspot mutant missplicing in cancer.

Xing P, Bak-Gordon P, Xie J, Zhang J, Liu Z, Manley J bioRxiv. 2025; .

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SF3B1: from core splicing factor to oncogenic driver.

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Molecular impact of mutations in RNA splicing factors in cancer.

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References

Sun P, Zhong Z, Lu Q, Li M, Chao X, Chen D . Mucinous carcinoma with micropapillary features is morphologically, clinically and genetically distinct from pure mucinous carcinoma of breast. Mod Pathol. 2020; 33(10):1945-1960. DOI: 10.1038/s41379-020-0554-8. View

Mihaly S, Ninomiya-Tsuji J, Morioka S . TAK1 control of cell death. Cell Death Differ. 2014; 21(11):1667-76. PMC: 4211365. DOI: 10.1038/cdd.2014.123. View

Liu Z, Zhang J, Sun Y, Perea-Chamblee T, Manley J, Rabadan R . Pan-cancer analysis identifies mutations in that recapitulate mutant SF3B1 splicing dysregulation. Proc Natl Acad Sci U S A. 2020; 117(19):10305-10312. PMC: 7229667. DOI: 10.1073/pnas.1922622117. View

Boj S, Hwang C, Baker L, Chio I, Engle D, Corbo V . Organoid models of human and mouse ductal pancreatic cancer. Cell. 2015; 160(1-2):324-38. PMC: 4334572. DOI: 10.1016/j.cell.2014.12.021. View

Tripathi V, Shin J, Stuelten C, Zhang Y . TGF-β-induced alternative splicing of TAK1 promotes EMT and drug resistance. Oncogene. 2019; 38(17):3185-3200. PMC: 6486402. DOI: 10.1038/s41388-018-0655-8. View

Je E, Yoo N, Kim Y, Kim M, Lee S . Mutational analysis of splicing machinery genes SF3B1, U2AF1 and SRSF2 in myelodysplasia and other common tumors. Int J Cancer. 2013; 133(1):260-5. DOI: 10.1002/ijc.28011. View

David C, Huang Y, Chen M, Su J, Zou Y, Bardeesy N . TGF-β Tumor Suppression through a Lethal EMT. Cell. 2016; 164(5):1015-30. PMC: 4801341. DOI: 10.1016/j.cell.2016.01.009. View

Chang A, Zhou Y, Iyengar S, Pobiarzyn P, Tishchenko P, Shah K . Modulation of SF3B1 in the pre-mRNA spliceosome induces a RIG-I-dependent type I IFN response. J Biol Chem. 2021; 297(5):101277. PMC: 8559577. DOI: 10.1016/j.jbc.2021.101277. View

Hezel A, Deshpande V, Zimmerman S, Contino G, Alagesan B, ODell M . TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression. Cancer Res. 2012; 72(18):4840-5. PMC: 3764481. DOI: 10.1158/0008-5472.CAN-12-0634. View

10.

Liu Z, Yoshimi A, Wang J, Cho H, Chun-Wei Lee S, Ki M . Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization. Cancer Discov. 2020; 10(6):806-821. PMC: 8188517. DOI: 10.1158/2159-8290.CD-19-1330. View

11.

Obeng E, Chappell R, Seiler M, Chen M, Campagna D, Schmidt P . Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation. Cancer Cell. 2016; 30(3):404-417. PMC: 5023069. DOI: 10.1016/j.ccell.2016.08.006. View

12.

Li Z, Zhao B, Shi Y, Liang Y, Qian R, Wan Y . Characterization of the aberrant splicing of MAP3K7 induced by cancer-associated SF3B1 mutation. J Biochem. 2021; 170(1):69-77. DOI: 10.1093/jb/mvab023. View

13.

Kesarwani A, Ramirez O, Gupta A, Yang X, Murthy T, Minella A . Cancer-associated SF3B1 mutants recognize otherwise inaccessible cryptic 3' splice sites within RNA secondary structures. Oncogene. 2016; 36(8):1123-1133. PMC: 5311031. DOI: 10.1038/onc.2016.279. View

14.

Mukhopadhyay H, Lee N . Multifaceted roles of TAK1 signaling in cancer. Oncogene. 2019; 39(7):1402-1413. PMC: 7023988. DOI: 10.1038/s41388-019-1088-8. View

15.

Furney S, Pedersen M, Gentien D, Dumont A, Rapinat A, Desjardins L . SF3B1 mutations are associated with alternative splicing in uveal melanoma. Cancer Discov. 2013; 3(10):1122-1129. PMC: 5321577. DOI: 10.1158/2159-8290.CD-13-0330. View

16.

Alsafadi S, Houy A, Battistella A, Popova T, Wassef M, Henry E . Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nat Commun. 2016; 7:10615. PMC: 4743009. DOI: 10.1038/ncomms10615. View

17.

Miao Y, Zou Y, Gu D, Zhu H, Zhu H, Wang L . mutation predicts unfavorable treatment-free survival in Chinese chronic lymphocytic leukemia patients. Ann Transl Med. 2019; 7(8):176. PMC: 6526254. DOI: 10.21037/atm.2019.03.63. View

18.

Liu B, Liu Z, Chen S, Ki M, Erickson C, Reis-Filho J . Mutant SF3B1 promotes AKT- and NF-κB-driven mammary tumorigenesis. J Clin Invest. 2020; 131(1). PMC: 7773370. DOI: 10.1172/JCI138315. View

19.

Hingorani S, Wang L, Multani A, Combs C, Deramaudt T, Hruban R . Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005; 7(5):469-83. DOI: 10.1016/j.ccr.2005.04.023. View

20.

Zhang J, Ali A, Lieu Y, Liu Z, Gao J, Rabadan R . Disease-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1. Mol Cell. 2019; 76(1):82-95.e7. PMC: 7065273. DOI: 10.1016/j.molcel.2019.07.017. View