A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets.
Although cancer-associated fibroblasts (CAFs) are viewed as a promising therapeutic target, the design of rational therapy has been hampered by two key obstacles. First, attempts to ablate CAFs have resulted in significant toxicity because currently used biomarkers cannot effectively distinguish activated CAFs from non-cancer associated fibroblasts and mesenchymal progenitor cells. Second, it is unclear whether CAFs in different organs have different molecular and functional properties that necessitate organ-specific therapeutic designs. Our analyses uncovered COL11A1 as a highly specific biomarker of activated CAFs. Using COL11A1 as a 'seed', we identified co-expressed genes in 13 types of primary carcinoma in The Cancer Genome Atlas. We demonstrated that a molecular signature of activated CAFs is conserved in epithelial cancers regardless of organ site and transforming events within cancer cells, suggesting that targeting fibroblast activation should be effective in multiple cancers. We prioritized several potential pan-cancer therapeutic targets that are likely to have high specificity for activated CAFs and minimal toxicity in normal tissues.
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Dongyu
D
Jia
Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Zhenqiu
Z
Liu
Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Nan
N
Deng
Cancer Science Institute of Singapore, Center for Translational Medicine, National University of Singapore, Singapore.
Tuan Zea
TZ
Tan
Cancer Science Institute of Singapore, Center for Translational Medicine, National University of Singapore, Singapore.
Ruby Yun-Ju
RY
Huang
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Barbie
B
Taylor-Harding
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY, USA.
Dong-Joo
DJ
Cheon
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Kate
K
Lawrenson
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Wolf R
WR
Wiedemeyer
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Ann E
AE
Walts
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
Beth Y
BY
Karlan
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Electronic address: Sandra.Orsulic@cshs.org.
Sandra
S
Orsulic
D000199:Actins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D030541:Databases, Genetic; D018572:Disease-Free Survival; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D013997:Time Factors; D059467:Transcriptome; D059016:Tumor Microenvironment
C541116:ACTA2 protein, human; D000199:Actins; D014408:Biomarkers, Tumor; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain
Cancer-associated fibroblasts; Myofibroblasts; Pan-cancer; Therapeutic targets; Tumor microenvironment