Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity

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-Canales, Jacob Albritton, Michael Weiger, Xin Liu, Hou Fu Guo, Jiang Yu, B. Leticia Rodriguez, Joshua J.A. Firestone, Barbara MinoChad 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

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish
Article number109009
JournalCell Reports
Issue number3
StatePublished - 20 Apr 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)


  • EMT
  • cancer-associated fibroblast
  • invasion
  • lung cancer
  • metastasis
  • microRNA
  • secretion
  • single-cell RNA sequencing
  • tumor microenvironment


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