SMAD4 represses FOSL1 expression and pancreatic cancer metastatic colonization

Chao Dai, Jonathan P. Rennhack, Taylor E. Arnoff, Maneesha Thaker, Scott T. Younger, John G. Doench, August Yue Huang, Annan Yang, Andrew J. Aguirre, Belinda Wang, Evan Mun, Joyce T. O'Connell, Ying Huang, Katherine Labella, Jessica A. Talamas, Ji Li, Nina Ilic, Justin Hwang, Andrew L. Hong, Andrew O. GiacomelliOle Gjoerup, David E. Root, William C. Hahn

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19 Scopus citations

Abstract

Metastasis is a complex and poorly understood process. In pancreatic cancer, loss of the transforming growth factor (TGF)-β/BMP effector SMAD4 is correlated with changes in altered histopathological transitions, metastatic disease, and poor prognosis. In this study, we use isogenic cancer cell lines to identify SMAD4 regulated genes that contribute to the development of metastatic colonization. We perform an in vivo screen identifying FOSL1 as both a SMAD4 target and sufficient to drive colonization to the lung. The targeting of these genes early in treatment may provide a therapeutic benefit.

Original languageEnglish (US)
Article number109443
JournalCell reports
Volume36
Issue number4
DOIs
StatePublished - Jul 27 2021

Bibliographical note

Funding Information:
This work was supported by the National Cancer Institute’s Office of Cancer Genomics Cancer Target Discovery and Development (CTD 2 ) initiative ( U01 CA176058 to W.C.H.) as well as AACR Basic Cancer Research postdoctoral fellowship 15-40-01-DAIC , an American Cancer Society postdoctoral fellowship PF-17-207-01-CSM (to C.D.), NCI grant K00 CA212221 (to J.P.R), American Cancer Society Mentored Research Scholar Grant MRSG-18-202-01 , and by Department of Defense CDMRP W81XWH-19-1-0281 (to A.L.H.). We thank Quang-De Nguyen from the Lurie Family Imaging Center and Catherine Sypher from the DFCI Animal Research Facility for assistance with imaging. The authors would like to thank members of the Hahn and Cichowski labs for their helpful comments.

Funding Information:
This work was supported by the National Cancer Institute's Office of Cancer Genomics Cancer Target Discovery and Development (CTD2) initiative (U01 CA176058 to W.C.H.) as well as AACR Basic Cancer Research postdoctoral fellowship 15-40-01-DAIC, an American Cancer Society postdoctoral fellowship PF-17-207-01-CSM (to C.D.), NCI grant K00 CA212221 (to J.P.R), American Cancer Society Mentored Research Scholar Grant MRSG-18-202-01, and by Department of Defense CDMRP W81XWH-19-1-0281 (to A.L.H.). We thank Quang-De Nguyen from the Lurie Family Imaging Center and Catherine Sypher from the DFCI Animal Research Facility for assistance with imaging. The authors would like to thank members of the Hahn and Cichowski labs for their helpful comments. C.D. J.P.R. and W.C.H. designed the study. C.D. J.P.R, J.A.T. and W.C.H. wrote the manuscript. C.D. J.P.R. T.E.A. M.T. E.M. A.Y. Y.H. and K.L. performed the experiments. C.D. J.P.R. and A.Y.H. analyzed the data. Y.H. assisted in data analysis. S.T.Y. J.G.D. and D.E.R. contributed advice on screening and data analysis. A.J.A. B.W. J.T.O. J.L. N.I. J.H. A.L.H. A.O.G. and O.G. contributed insights. W.C.H. supervised the design and the execution of this study. All authors discussed the findings and edited the manuscript. W.C.H. is a consultant for Thermo Fisher Scientific, Solasta Ventures, MPM Capital, KSQ Therapeutics, iTeos, Tyra Biosciences, iTeos, Frontier Medicines, Jubliant Therapeutics, RAPPTA Therapeutics, and Paraxel. A.J.A. has consulted for Oncorus, Inc. Arrakis Therapeutics, and Merck & Co. Inc. and has research funding from Mirati Therapeutics and Deerfield, Inc. that is unrelated to this project. A.O.G. is a share and option holder of 10X Genomics. The remaining authors declare no competing interests.

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • FOSL1
  • PDAC
  • SMAD4
  • colonization
  • metastasis

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