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TGF-β and RAS jointly unmask primed enhancers to drive metastasis

Affiliations
  • 1Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 3Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona 08028, Spain.
  • 4Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Tri-Institutional Graduate Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 8Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona 08028, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
  • 9Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 10Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: massaguj@mskcc.org.

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September 7, 2024

Abstract

Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF-β) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS inputs. RREB1 localizes to H4K16acK20ac marks in histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes interleukin-11 (IL11), platelet-derived growth factor-B (PDGFB), and hyaluronan synthase 2 (HAS2), as well as the EMT transcription factor SNAI1, priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-β. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-β gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth.

Keywords:

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