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 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

doi:10.1016/j.celrep.2021.109009

Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity

Cell Rep. 2021 Apr 20;35(3):109009. doi: 10.1016/j.celrep.2021.109009.

Authors

Neus Bota-Rabassedas¹, Priyam Banerjee¹, Yichi Niu², Wenjian Cao², Jiayi Luo², Yuanxin Xi³, Xiaochao Tan¹, Kuanwei Sheng², Young-Ho Ahn⁴, Sieun Lee⁴, Edwin Roger Parra⁵, Jaime Rodriguez-Canales⁵, Jacob Albritton⁴, Michael Weiger⁶, Xin Liu¹, Hou-Fu Guo¹, Jiang Yu¹, B Leticia Rodriguez¹, Joshua J A Firestone⁷, Barbara Mino⁵, Chad J Creighton⁸, Luisa M Solis⁵, Pamela Villalobos⁵, Maria Gabriela Raso⁵, Daniel W Sazer⁹, Don L Gibbons¹, William K Russell¹⁰, Gregory D Longmore¹¹, Ignacio I Wistuba⁵, Jing Wang³, Harold A Chapman¹², Jordan S Miller¹³, Chenghang Zong¹⁴, Jonathan M Kurie¹⁵

Affiliations

¹ Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
³ Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul 07804, Korea.
⁵ Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Houston, TX, USA.
⁸ Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁹ Department of Bioengineering, Rice University, Houston, TX, USA.
¹⁰ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
¹¹ Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Department of Cell Biology & Physiology, Washington University in St. Louis, St. Louis, MO, USA.
¹² Department of Medicine, University of California, San Francisco Cardiovascular Research Institute, San Francisco, CA, USA.
¹³ Department of Bioengineering, Rice University, Houston, TX, USA. Electronic address: jmil@rice.edu.
¹⁴ Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: chenghang.zong@bcm.edu.
¹⁵ Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jkurie@mdanderson.org.

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.

Keywords: EMT; cancer-associated fibroblast; invasion; lung cancer; metastasis; microRNA; secretion; single-cell RNA sequencing; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung / genetics*
Adenocarcinoma of Lung / metabolism
Adenocarcinoma of Lung / secondary
Alpha-Globulins / genetics
Alpha-Globulins / metabolism
Animals
Cancer-Associated Fibroblasts / metabolism*
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 / metabolism*
Epithelial Cells / pathology
Epithelial-Mesenchymal Transition / genetics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Kidney Neoplasms / genetics*
Kidney Neoplasms / metabolism
Kidney Neoplasms / secondary
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Male
Mesenchymal Stem Cells / metabolism*
Mesenchymal Stem Cells / pathology
Mice
Mice, Transgenic
Signal Transduction
Tumor Microenvironment / genetics
Zinc Finger E-box-Binding Homeobox 1 / genetics*
Zinc Finger E-box-Binding Homeobox 1 / metabolism

Substances

Alpha-Globulins
ZEB1 protein, human
Zinc Finger E-box-Binding Homeobox 1
inter-alpha-inhibitor
DDR2 protein, human
Discoidin Domain Receptor 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding