TGF-β Tumor Suppression through a Lethal EMT

Cell
Charles J DavidJoan Massagué

Abstract

TGF-β signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-β mediator Smad4. We show that TGF-β induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-β-sensitive PDA cells, EMT becomes lethal by converting TGF-β-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-β. TGF-β-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-β tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.

References

Jun 6, 1998·Science·J R HoweL A Aaltonen
Jan 7, 2004·Cancer Cell·Sunil R HingoraniDavid A Tuveson
Feb 24, 2004·Molecular Pharmacology·Stacey DaCosta ByfieldAnita B Roberts
Jul 30, 2008·Cell·Joan Massagué
Mar 11, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Christine A Iacobuzio-DonahueDaniel Laheru
Jul 31, 2009·Oncogene·J D PiñonA Villunger
Dec 1, 2009·Cell·Jean Paul ThieryM Angela Nieto
Oct 18, 2011·Cell·Scott Valastyan, Robert A Weinberg
Jan 24, 2012·Cell·Andrew D RhimBen Z Stanger
Mar 13, 2012·Molecular and Cellular Endocrinology·Ezra Wiater, Wylie Vale
Jun 20, 2012·FEBS Letters·Carl-Henrik HeldinAristidis Moustakas
Sep 21, 2012·Nature Reviews. Molecular Cell Biology·Joan Massagué
Dec 12, 2012·Cell Stem Cell·Naoki Oshimori, Elaine Fuchs
Mar 19, 2013·Cell·Tong Ihn Lee, Richard A Young
Aug 13, 2013·Gene·A A StepanenkoV M Kavsan
Nov 5, 2013·Cancer Cell·Hong ZhangDaniel G Tenen
Dec 18, 2013·Cell Reports·Christof FellmannJohannes Zuber
Jan 8, 2014·Genes & Development·Michael SaborowskiScott W Lowe
Feb 8, 2014·Seminars in Cell & Developmental Biology·Tessa Gaarenstroom, Caroline S Hill
Mar 15, 2014·Cancer Research·Takeo NakayaRyozo Nagai
Jan 6, 2015·Cell·Sylvia F BojDavid A Tuveson
Apr 8, 2015·World Journal of Gastrointestinal Surgery·Fábio Guilherme CamposCarlos Augusto Real Martinez

❮ Previous
Next ❯

Citations

Feb 27, 2016·Cell·Sonal Gupta, Anirban Maitra
Jun 14, 2016·Molecular Cell·Dafni-Eleftheria PefaniEric O' Neill
Jun 28, 2016·Pharmacology & Therapeutics·Daniel DelittoSteven J Hughes
Jul 2, 2016·Cell·M Angela NietoJean Paul Thiery
Jul 2, 2016·Journal of Clinical Medicine·Aristidis Moustakas, Carl-Henrik Heldin
Jul 14, 2016·Cell Biology and Toxicology·Xiangdong Wang
Sep 19, 2016·Seminars in Cell & Developmental Biology·Lingyan WangXiangdong Wang
Nov 5, 2016·Nature Reviews. Drug Discovery·Yufang ShiYing Wang
Dec 31, 2016·The Journal of Pathology·Ke JinLong Zhang
Mar 16, 2017·Genes & Development·Adam T BoutinRonald A DePinho
Apr 4, 2017·Gastroenterology·Chang-Kyung KimVincent W Yang
Jul 19, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Xu SunXue-Li Bai
Dec 6, 2017·Acta Biochimica Et Biophysica Sinica·Fanglong WuXiao-Jing Wang
Dec 1, 2017·Acta Biochimica Et Biophysica Sinica·Feng XieLong Zhang
Dec 1, 2017·Nucleic Acids Research·Anders SundqvistPeter Ten Dijke
Apr 13, 2018·Nature Reviews. Molecular Cell Biology·Charles J David, Joan Massagué
Nov 18, 2017·Nature Communications·Alice C NewmanSimon Wilkinson
Mar 2, 2017·Cold Spring Harbor Perspectives in Biology·Joan Seoane, Roger R Gomis
Jan 31, 2018·BioMed Research International·Shuai WangYu Ling Sun
Apr 25, 2018·Cancer Research and Treatment : Official Journal of Korean Cancer Association·Jianhui CaiXiangbin Wu
Sep 6, 2018·The Journal of Clinical Investigation·Youwei WangJianhua Yu
Nov 6, 2018·Journal of Cellular and Molecular Medicine·Ziyan ChenGang Chen
Nov 2, 2018·Histochemistry and Cell Biology·Eric Bekoe OffeiBeate Brand-Saberi
Jul 18, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jinqiang ZhangTong Wu
Sep 26, 2017·Nature Cell Biology·Julia Varga, Florian R Greten
Mar 5, 2016·Nature Reviews. Molecular Cell Biology·Paulina Strzyz
May 30, 2019·Molecular Carcinogenesis·Ariel L HernandezXiao-Jing Wang
May 26, 2016·EMBO Molecular Medicine·Evelyn FesslerJan Paul Medema
Aug 11, 2017·Cell & Bioscience·Wei ShenZhi-Qiang Tian
Nov 11, 2019·Scientific Reports·Peipei PanMatilda F Chan

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Cell eTOC

Cell is a scientific journal publishing research across a broad range of disciplines within the life sciences field. Discover the latest research from Cell here.