Identifying distinct prognostic and predictive contributions of tumor epithelium versus tumor microenvironment in colorectal cancer

Mingli Yang ¹, Michael V Nebozhyn ², Michael J Schell ³

¹Department of Surgery, University of South Florida, 560 Channelside Drive, Tampa, FL, 33602, USA. mingliyang@usf.edu.
²Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA, 02115, USA.
³Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
⁴Medical Affairs, Caris Life Sciences, 4610 S 44th Pl, Phoenix, AZ, 85040, USA.
⁵Phenome Health, 401 Terry Ave N, Seattle, WA, 98109, USA.
⁶Department of Molecular Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, Tampa, FL, 33612, USA.
⁷Tampa General Hospital Cancer Institute, 1 Tampa General Circle, Tampa, FL, 33606, USA.
⁸Department of Surgery, University of South Florida, 560 Channelside Drive, Tampa, FL, 33602, USA.
⁹Department of Pathology, Florida Digestive Health Specialists, 10920 Technology Ter, Lakewood Ranch, FL, 34202, USA.
¹⁰Department of Pathology, Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
¹¹Division of Medical Oncology, Department of Medicine, Washington University, 4590 Nash Way, St. Louis, MO, 63110, USA.
¹²Division of Hematology, Oncology and Transplantation, Department of Medicine and Masonic Cancer Center, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN, 55455, USA.
¹³Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson School of Medicine, 195 Little Albany Street, New Brunswick, NJ, 08903, USA.
¹⁴Department of Surgery, University of South Florida, 560 Channelside Drive, Tampa, FL, 33602, USA. tyeatman@usf.edu.
¹⁵Department of Molecular Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, Tampa, FL, 33612, USA. tyeatman@usf.edu.
¹⁶Tampa General Hospital Cancer Institute, 1 Tampa General Circle, Tampa, FL, 33606, USA. tyeatman@usf.edu.

⁰Department of Surgery, University of South Florida, 560 Channelside Drive, Tampa, FL, 33602, USA. mingliyang@usf.edu.

Bmc Cancer +

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March 13, 2025

View abstract on PubMed

Summary

New 10-gene signatures, EPI<sup>S</sup> and TME<sup>S</sup>, distinguish tumor epithelium and microenvironment contributions to colorectal cancer prognosis and treatment response, aiding therapy optimization.

Area Of Science

Oncology
Genomics
Cancer Biology

Background

Tumor progression and treatment response involve both tumor epithelium (EPI) and the tumor microenvironment (TME).
The distinct contributions of EPI versus TME to clinical outcomes in colorectal cancer (CRC) remain poorly defined and quantified.

Purpose Of The Study

To develop and validate novel gene signatures that can differentiate the cellular contributions of the tumor EPI and TME.
To assess the prognostic and predictive value of these signatures in colorectal cancer.

Main Methods

Classified 2373 CRC tumors into consensus molecular subtypes (CMS1-4).
Generated 10-gene TME<sup>S</sup> and EPI<sup>S</sup> signatures derived from a previously identified prognostic gene signature.
Utilized CIBERSORT deconvolution and scRNASEQ for cellular feature identification and validation.

Main Results

TME<sup>S</sup> signature associated with immune/stromal-rich, poor-prognosis CMS1/CMS4 subtypes and cancer-associated fibroblasts.
EPI<sup>S</sup> signature linked to epithelial-rich, better-prognosis CMS2/CMS3 subtypes.
EPI<sup>S</sup> scores correlated with improved progression-free survival in cetuximab-treated CRC patients and overall survival in EGFR inhibitor-treated patients.

Conclusions

Identified distinct 10-gene EPI<sup>S</sup> and TME<sup>S</sup> signatures for differentiating tumor EPI and TME contributions to CRC outcomes.
These signatures may serve as novel biomarkers for optimizing CRC therapy by identifying sensitive and resistant subpopulations.

Keywords:

Cetuximab Clinical outcome Colorectal cancer Consensus molecular subtype EGFR inhibitor Gene expression signature MEK inhibitor Panitumumab Tumor epithelium Tumor microenvironment

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