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Memorial Sloan Kettering Cancer Center

Cell, September 06, 2024 | https://doi.org/10.1016/j.cell.2024.08.014 TGF-β and RAS jointly unmask primed enhancers to drive metastasis

Jun Ho Lee,¹ Francisco J. Sa´ nchez-Rivera,^1,9,10 Lan He,¹ Harihar Basnet,^1,11 Fei Xavier Chen,^1,12 Elena Spina,¹Liangji Li,^1,13 Carles Torner,² Jason E. Chan,^1,3 Dig Vijay Kumar Yarlagadda,^4,5 Jin Suk Park,¹ Carleigh Sussman,¹Charles M. Rudin,³ Scott W. Lowe,^1,6 Tuomas Tammela,¹ Maria J. Macias,^2,7 Richard P. Koche,⁸ and Joan Massague´ ^1,14,*

¹Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

²Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona 08028, Spain

³Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

⁴Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

⁵Tri-Institutional Graduate Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY 10065, USA

⁶Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

⁷Institucio´ Catalana de Recerca i Estudis Avanc¸ ats (ICREA), Barcelona 08010, Spain

⁸Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

⁹Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

¹⁰Present address: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

¹¹Present address: Tsinghua University School of Medicine, Department of Basic Sciences, Beijing 100084, P.R. China

¹²Present address: Institute of Biomedical Sciences and Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China

¹³Present address: State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China

¹⁴Lead contact

^*Corresponding author: correspondence to Joan Massague´

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.

논문정보

형식Research article
게재일2024년 09월 (BRIC 등록일 2024-09-10)
연구진국외 연구진
분야 생명과학 > 노화/암생물학

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