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

6 Scopus citations

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.

Original languageEnglish
Article number109009
JournalCell Reports
Volume35
Issue number3
DOIs
StatePublished - Apr 20 2021

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) grants R01 CA181184 (to J.M.K.), R01 CA2111125 (to J.M.K.), P30 CA125123 (to C.J.C.), R01 CA196205 (to G.D.L.); Department of Defense PROSPECT grant W81XWH-07-1-0306 (to I.I.W.); National Cancer Institute (NCI) Specialized Program of Research Excellence (SPORE) grant 1-P50-CA70907-01 ; CPRIT-MIRA grant RP160652 (to J.M.K.); and National Research Foundation of Korea (NRF) grant NRF-2020R1A5A2019210 (to Y.-H.A.). NCI P30 CA16672 Core grant supported flow cytometry. J.M.K. holds the Gloria Lupton Tennison Distinguished Professorship in Lung Cancer. C.Z. is supported by a McNair Scholarship . D.L.G. is an R. Lee Clark Fellow of the University of Texas MD Anderson Cancer Center, supported by the Jeane F Shelby Scholarship Fund . This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award ( CPRIT-RP180672 ), the NIH ( P30 CA125123 and S10 RR024574 ), and the expert assistance of Joel M. Sederstrom. The UTMB Mass Spectrometry Facility is supported in part by CPRIT grant RP190682 (to W.K.R.).

Funding Information:
This work was supported by National Institutes of Health (NIH) grants R01 CA181184 (to J.M.K.), R01 CA2111125 (to J.M.K.), P30 CA125123 (to C.J.C.), R01 CA196205 (to G.D.L.); Department of Defense PROSPECT grant W81XWH-07-1-0306 (to I.I.W.); National Cancer Institute (NCI) Specialized Program of Research Excellence (SPORE) grant 1-P50-CA70907-01; CPRIT-MIRA grant RP160652 (to J.M.K.); and National Research Foundation of Korea (NRF) grant NRF-2020R1A5A2019210 (to Y.-H.A.). NCI P30 CA16672 Core grant supported flow cytometry. J.M.K. holds the Gloria Lupton Tennison Distinguished Professorship in Lung Cancer. C.Z. is supported by a McNair Scholarship. D.L.G. is an R. Lee Clark Fellow of the University of Texas MD Anderson Cancer Center, supported by the Jeane F Shelby Scholarship Fund. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (P30 CA125123 and S10 RR024574), and the expert assistance of Joel M. Sederstrom. The UTMB Mass Spectrometry Facility is supported in part by CPRIT grant RP190682 (to W.K.R.). N.B.-R. designed, executed, and interpreted 3D culture, cell culture, in vivo experiments, and performed and interpreted confocal microscopy. P.B. assisted N.B.-R. with the co-culture model design and confocal microscopy and performed and interpreted the live-cell imaging. Y.N. and J.L. performed the single-cell RNA-seq studies. K.S. performed the mini-bulk RNA-seq experiments. W.C. and Y.N. performed the bioinformatic analysis of the RNA-seq data. C.Z. supervised the single-cell RNA-seq experiments and analysis. J.A. D.W.S. and J.S.M. generated the microwell plates used in the co-culture models. Y.X. J.W. and C.J.C. analyzed the RNA-seq data. M.W. assisted with the design of the co-culture model. X.L. X.T. H.-F.G. Y.-H.A. S.L. and J.Y. assisted with the studies on cell culture and in vivo models. J.J.A.F. assisted with RNA-seq data handling and organization. B.L.R. and D.L.G. performed the flow cytometric analyses on orthotopic lung tumors. G.D.L. provided useful input into the experimental design and interpretation of findings from the DDR2 experiments. E.R.P. J.R.-C. B.M. L.M.S. P.V. M.G.R. H.A.C. and I.I.W. provided the data on human LUADs that were removed from the manuscript during the review process. J.M.K. conceived and supervised the project and contributed to the design and interpretation of all of the experiments. 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.

Funding Information:
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.

Publisher Copyright:
© 2021 The Author(s)

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)

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