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

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

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

10 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 language	English (US)
Article number	109009
Journal	Cell Reports
Volume	35
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.109009
State	Published - Apr 20 2021

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)

Access to Document

10.1016/j.celrep.2021.109009

Cite this

Bota-Rabassedas, N., Banerjee, P., Niu, Y., Cao, W., Luo, J., Xi, Y., Tan, X., Sheng, K., Ahn, Y. H., Lee, S., Parra, E. R., Rodriguez-Canales, J., Albritton, J., Weiger, M., Liu, X., Guo, H. F., Yu, J., Rodriguez, B. L., Firestone, J. J. A., ... Kurie, J. M. (2021). Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity. Cell Reports, 35(3), Article 109009. https://doi.org/10.1016/j.celrep.2021.109009

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 & Kurie, JM 2021, 'Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity', Cell Reports, vol. 35, no. 3, 109009. https://doi.org/10.1016/j.celrep.2021.109009

@article{e09e230d3fda4ef19fd6bec13ead06dd,

title = "Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity",

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",

author = "Neus Bota-Rabassedas and Priyam Banerjee and Yichi Niu and Wenjian Cao and Jiayi Luo and Yuanxin Xi and Xiaochao Tan and Kuanwei Sheng and Ahn, {Young Ho} and Sieun Lee and Parra, {Edwin Roger} and Jaime Rodriguez-Canales and Jacob Albritton and Michael Weiger and Xin Liu and Guo, {Hou Fu} and Jiang Yu and Rodriguez, {B. Leticia} and Firestone, {Joshua J.A.} and Barbara Mino and Creighton, {Chad J.} and Solis, {Luisa M.} and Pamela Villalobos and Raso, {Maria Gabriela} and Sazer, {Daniel W.} and Gibbons, {Don L.} and Russell, {William K.} and Longmore, {Gregory D.} and Wistuba, {Ignacio I.} and Jing Wang and Chapman, {Harold A.} and Miller, {Jordan S.} and Chenghang Zong and Kurie, {Jonathan M.}",

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: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = apr,

day = "20",

doi = "10.1016/j.celrep.2021.109009",

language = "English (US)",

volume = "35",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity

AU - Bota-Rabassedas, Neus

AU - Banerjee, Priyam

AU - Niu, Yichi

AU - Cao, Wenjian

AU - Luo, Jiayi

AU - Xi, Yuanxin

AU - Tan, Xiaochao

AU - Sheng, Kuanwei

AU - Ahn, Young Ho

AU - Lee, Sieun

AU - Parra, Edwin Roger

AU - Rodriguez-Canales, Jaime

AU - Albritton, Jacob

AU - Weiger, Michael

AU - Liu, Xin

AU - Guo, Hou Fu

AU - Yu, Jiang

AU - Rodriguez, B. Leticia

AU - Firestone, Joshua J.A.

AU - Mino, Barbara

AU - Creighton, Chad J.

AU - Solis, Luisa M.

AU - Villalobos, Pamela

AU - Raso, Maria Gabriela

AU - Sazer, Daniel W.

AU - Gibbons, Don L.

AU - Russell, William K.

AU - Longmore, Gregory D.

AU - Wistuba, Ignacio I.

AU - Wang, Jing

AU - Chapman, Harold A.

AU - Miller, Jordan S.

AU - Zong, Chenghang

AU - Kurie, Jonathan M.

N1 - 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)

PY - 2021/4/20

Y1 - 2021/4/20

N2 - 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.

AB - 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.

KW - EMT

KW - cancer-associated fibroblast

KW - invasion

KW - lung cancer

KW - metastasis

KW - microRNA

KW - secretion

KW - single-cell RNA sequencing

KW - tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85104303878&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85104303878&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.109009

DO - 10.1016/j.celrep.2021.109009

M3 - Article

C2 - 33882319

AN - SCOPUS:85104303878

SN - 2211-1247

VL - 35

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 109009

ER -

Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this