KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix

Jin K. Kim; Michael R. Marco; Seo Hyun Choi; Xuan Qu; Chin Tung Chen; Moshe Elkabets; Lauren Fairchild; Oliver Chow; Francisco M. Barriga; Lukas E. Dow; Kevin O’Rourke; Bryan Szeglin; Dmitry Yarilin; Sho Fujisawa; Katia Manova-Todorova; Philip B. Paty; Jinru Shia; Christina Leslie; J. Joshua Smith; Scott Lowe; Raphael Pelossof; Francisco Sanchez-Vega; Julio Garcia-Aguilar

doi:10.1002/1878-0261.12960

KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix

Jin K. Kim, Michael R. Marco, Seo Hyun Choi, Xuan Qu, Chin Tung Chen, Moshe Elkabets, Lauren Fairchild, Oliver Chow, Francisco M. Barriga, Lukas E. Dow, Kevin O’Rourke, Bryan Szeglin, Dmitry Yarilin, Sho Fujisawa, Katia Manova-Todorova, Philip B. Paty, Jinru Shia, Christina Leslie, J. Joshua Smith, Scott LoweRaphael Pelossof, Francisco Sanchez-Vega, Julio Garcia-Aguilar

The Shraga Segal Department of Microbiology and Immunology

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

6 Scopus citations

Abstract

Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS-mt) and KRAS-wild-type (KRAS-wt) patients. We found that KRAS-mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment.

Original language	English
Pages (from-to)	2766-2781
Number of pages	16
Journal	Molecular Oncology
Volume	15
Issue number	10
DOIs	https://doi.org/10.1002/1878-0261.12960
State	Published - 1 Oct 2021

Keywords

KRAS
cancer-associated fibroblast
extracellular matrix
rectal cancer
tumor response
tumor stroma

ASJC Scopus subject areas

Molecular Medicine
Oncology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/1878-0261.12960

Cite this

Kim, J. K., Marco, M. R., Choi, S. H., Qu, X., Chen, C. T., Elkabets, M., Fairchild, L., Chow, O., Barriga, F. M., Dow, L. E., O’Rourke, K., Szeglin, B., Yarilin, D., Fujisawa, S., Manova-Todorova, K., Paty, P. B., Shia, J., Leslie, C., Joshua Smith, J., ... Garcia-Aguilar, J. (2021). KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix. Molecular Oncology, 15(10), 2766-2781. https://doi.org/10.1002/1878-0261.12960

@article{6d93f2ad69e24fb88f5d49f181753e4c,

title = "KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix",

abstract = "Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS-mt) and KRAS-wild-type (KRAS-wt) patients. We found that KRAS-mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment.",

keywords = "KRAS, cancer-associated fibroblast, extracellular matrix, rectal cancer, tumor response, tumor stroma",

author = "Kim, {Jin K.} and Marco, {Michael R.} and Choi, {Seo Hyun} and Xuan Qu and Chen, {Chin Tung} and Moshe Elkabets and Lauren Fairchild and Oliver Chow and Barriga, {Francisco M.} and Dow, {Lukas E.} and Kevin O{\textquoteright}Rourke and Bryan Szeglin and Dmitry Yarilin and Sho Fujisawa and Katia Manova-Todorova and Paty, {Philip B.} and Jinru Shia and Christina Leslie and {Joshua Smith}, J. and Scott Lowe and Raphael Pelossof and Francisco Sanchez-Vega and Julio Garcia-Aguilar",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies",

year = "2021",

month = oct,

day = "1",

doi = "10.1002/1878-0261.12960",

language = "English",

volume = "15",

pages = "2766--2781",

journal = "Molecular Oncology",

issn = "1574-7891",

publisher = "John Wiley and Sons Ltd",

number = "10",

}

Kim, JK, Marco, MR, Choi, SH, Qu, X, Chen, CT, Elkabets, M, Fairchild, L, Chow, O, Barriga, FM, Dow, LE, O’Rourke, K, Szeglin, B, Yarilin, D, Fujisawa, S, Manova-Todorova, K, Paty, PB, Shia, J, Leslie, C, Joshua Smith, J, Lowe, S, Pelossof, R, Sanchez-Vega, F & Garcia-Aguilar, J 2021, 'KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix', Molecular Oncology, vol. 15, no. 10, pp. 2766-2781. https://doi.org/10.1002/1878-0261.12960

TY - JOUR

T1 - KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix

AU - Kim, Jin K.

AU - Marco, Michael R.

AU - Choi, Seo Hyun

AU - Qu, Xuan

AU - Chen, Chin Tung

AU - Elkabets, Moshe

AU - Fairchild, Lauren

AU - Chow, Oliver

AU - Barriga, Francisco M.

AU - Dow, Lukas E.

AU - O’Rourke, Kevin

AU - Szeglin, Bryan

AU - Yarilin, Dmitry

AU - Fujisawa, Sho

AU - Manova-Todorova, Katia

AU - Paty, Philip B.

AU - Shia, Jinru

AU - Leslie, Christina

AU - Joshua Smith, J.

AU - Lowe, Scott

AU - Pelossof, Raphael

AU - Sanchez-Vega, Francisco

AU - Garcia-Aguilar, Julio

PY - 2021/10/1

Y1 - 2021/10/1

N2 - Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS-mt) and KRAS-wild-type (KRAS-wt) patients. We found that KRAS-mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment.

AB - Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS-mt) and KRAS-wild-type (KRAS-wt) patients. We found that KRAS-mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment.

KW - KRAS

KW - cancer-associated fibroblast

KW - extracellular matrix

KW - rectal cancer

KW - tumor response

KW - tumor stroma

UR - http://www.scopus.com/inward/record.url?scp=85107844468&partnerID=8YFLogxK

U2 - 10.1002/1878-0261.12960

DO - 10.1002/1878-0261.12960

M3 - Article

C2 - 33817986

AN - SCOPUS:85107844468

SN - 1574-7891

VL - 15

SP - 2766

EP - 2781

JO - Molecular Oncology

JF - Molecular Oncology

IS - 10

ER -

KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this