1. Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity.
- Author
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Bota-Rabassedas N, Banerjee P, Niu Y, Cao W, Luo J, Xi Y, Tan X, Sheng K, Ahn YH, Lee S, Parra ER, Rodriguez-Canales J, Albritton J, Weiger M, Liu X, Guo HF, Yu J, Rodriguez BL, Firestone JJA, Mino B, Creighton CJ, Solis LM, Villalobos P, Raso MG, Sazer DW, Gibbons DL, Russell WK, Longmore GD, Wistuba II, Wang J, Chapman HA, Miller JS, Zong C, and Kurie JM
- Subjects
- Adenocarcinoma of Lung metabolism, Adenocarcinoma of Lung secondary, Alpha-Globulins genetics, Alpha-Globulins metabolism, Animals, Cancer-Associated Fibroblasts pathology, Cell Communication, Cell Line, Tumor, Cell Movement, Cell Proliferation, Discoidin Domain Receptor 2 genetics, Discoidin Domain Receptor 2 metabolism, Epithelial Cells pathology, Epithelial-Mesenchymal Transition genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms metabolism, Kidney Neoplasms secondary, Lung Neoplasms metabolism, Lung Neoplasms pathology, Male, Mesenchymal Stem Cells pathology, Mice, Mice, Transgenic, Signal Transduction, Tumor Microenvironment genetics, Zinc Finger E-box-Binding Homeobox 1 metabolism, Adenocarcinoma of Lung genetics, Cancer-Associated Fibroblasts metabolism, Epithelial Cells metabolism, Kidney Neoplasms genetics, Lung Neoplasms genetics, Mesenchymal Stem Cells metabolism, Zinc Finger E-box-Binding Homeobox 1 genetics
- Abstract
Cancer cells function as primary architects of the tumor microenvironment. However, the molecular features of cancer cells that govern stromal cell phenotypes remain unclear. Here, we show that cancer-associated fibroblast (CAF) heterogeneity is driven by lung adenocarcinoma (LUAD) cells at either end of the epithelial-to-mesenchymal transition (EMT) spectrum. LUAD cells that have high expression of the EMT-activating transcription factor ZEB1 reprogram CAFs through a ZEB1-dependent secretory program and direct CAFs to the tips of invasive projections through a ZEB1-driven CAF repulsion process. The EMT, in turn, sensitizes LUAD cells to pro-metastatic signals from CAFs. Thus, CAFs respond to contextual cues from LUAD cells to promote metastasis., Competing Interests: Declaration of interests D.L.G. serves on scientific advisory committees for AstraZeneca, GlaxoSmithKline, Sanofi, and Janssen; provides consultation to Ribon Therapeutics; and receives research support from Janssen, Takeda, and AstraZeneca. I.I.W. serves on advisory boards for Genentech/Roche, Bristol-Myers Squibb, Medscape, Astra Zeneca/Medimmune, HTG Molecular, Merck, GlaxoSmithKline, and MSD and receives research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, 4D, Novartis, and Perkin-Elmer (Akoya). G.D.L. has received financial support from Pfizer-CTI. J.M.K. has received consulting fees from Halozyme. P.B. has received consulting fees from ExpertConnect., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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