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 Giacomelli; Ole Gjoerup; David E Root; William C Hahn

doi:10.1016/j.celrep.2021.109443

SMAD4 represses FOSL1 expression and pancreatic cancer metastatic colonization

Cell Rep. 2021 Jul 27;36(4):109443. doi: 10.1016/j.celrep.2021.109443.

Authors

Chao Dai¹, Jonathan P Rennhack¹, Taylor E Arnoff², Maneesha Thaker³, Scott T Younger³, John G Doench³, August Yue Huang⁴, Annan Yang¹, Andrew J Aguirre¹, Belinda Wang¹, Evan Mun⁵, Joyce T O'Connell¹, Ying Huang⁶, Katherine Labella², Jessica A Talamas², Ji Li¹, Nina Ilic¹, Justin Hwang⁷, Andrew L Hong⁸, Andrew O Giacomelli⁹, Ole Gjoerup¹, David E Root³, William C Hahn¹⁰

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Northeastern University, Boston, MA 02115, USA.
⁶ Molecular Pathology Core Lab, Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁷ Masonic Cancer Center and Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA.
⁸ Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: [email protected].

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.

Keywords: FOSL1; PDAC; SMAD4; colonization; metastasis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / pathology
Animals
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / pathology
Cell Line, Tumor
Cell Proliferation / genetics
Enhancer Elements, Genetic / genetics
Gene Expression Regulation, Neoplastic*
Humans
Mice
Neoplasm Metastasis
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / pathology*
Proto-Oncogene Proteins c-fos / genetics*
Proto-Oncogene Proteins c-fos / metabolism
Smad4 Protein / metabolism*

Substances

Proto-Oncogene Proteins c-fos
SMAD4 protein, human
Smad4 Protein
fos-related antigen 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding