Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity

• DOI: 10.1016/j.celrep.2021.109009
• Publication Date: 2021-04-21T04:00:28Z
• Authors: Neus Bota-Rabassedas; Priyam Banerjee; Yichi Niu; Wenjian Cao; Jiayi Luo; Yuanxin Xi; Xiaochao Tan; Kuanwei Sheng; Young-Ho Ahn; Sieun Lee; Edwin Roger Parra; Jaime Rodriguez-C...; Jacob Albritton; Michael Weiger; Xin Liu; Hou-Fu Guo; Jiang Yu; B. Leticia Rodriguez; Joshua J.A. Fires...; Barbara Mino; Chad J. Creighton; Luisa M. Solis; Pamela Villalobos; Maria Gabriela Raso; Daniel W. Sazer; Don L. Gibbons; William K. Russell; Gregory D. Longmore; Ignacio I. Wistuba; Jing Wang; Harold A. Chapman; Jordan S. Miller; Chenghang Zong; Jonathan M. Kurie
• Keywords: Cancer-Associated Fibroblasts

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.