Seed and Soil: Consensus Molecular Subgroups (CMS) and Tumor Microenvironment Features Between Primary Lesions and Metastases of Different Organ Sites in Colorectal Cancer

Qingqing Luo; Yibo Quan; Wei Liu; Zixin Wu; Wenjing Qiu; Wenlong Liang; Ping Yang; Qing Huang; Guanwei Li; Jianchang Wei; Qiang Wang; Fei Shen; Wanglin Li; Feng He; Jie Cao

doi:10.2147/CMAR.S441675

Seed and Soil: Consensus Molecular Subgroups (CMS) and Tumor Microenvironment Features Between Primary Lesions and Metastases of Different Organ Sites in Colorectal Cancer

Cancer Manag Res. 2024 Mar 20:16:225-243. doi: 10.2147/CMAR.S441675. eCollection 2024.

Authors

Qingqing Luo^#¹, Yibo Quan^#¹, Wei Liu¹, Zixin Wu¹, Wenjing Qiu¹, Wenlong Liang¹, Ping Yang¹, Qing Huang¹, Guanwei Li¹, Jianchang Wei¹, Qiang Wang¹, Fei Shen², Wanglin Li¹, Feng He³, Jie Cao¹

Affiliations

¹ Department of Gastrointestinal Surgery, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People's Republic of China.
² Department of Thyroid Surgery, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People's Republic of China.
³ Department of Nephrology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: Consensus molecular subtypes (CMS) are mainly used for biological interpretability and clinical stratification of colorectal cancer (CRC) in primary tumors (PT) but few in metastases. The heterogeneity of CMS distribution in metastases and the concordance of CMS between PT and metastases still lack sufficient study. We used CMS to classify CRC metastases and combine it with histopathological analysis to explore differences between PT and distant metastases.

Patients and methods: We obtained gene expression profiles for 942 PT samples from TCGA database (n=376) and GEO database (n=566), as well as 442 metastasis samples from GEO database. Among these, 765 PT samples and 442 metastasis samples were confidently identified with CMS using the "CMS classifier" and enrolled for analysis. Clinicopathological manifestation and CMS classification of CRC metastases were assessed with data from GEO, TCGA, and cBioPortal. Overall, 105 PT-metastasis pairs were extracted from 10 GEO datasets to assess CMS concordance. Tumor microenvironment (TME) features between PT and metastases were analyzed by immune-stromal infiltration with ESTIMATE and xCell algorithms. Finally, TME features were validated with multiplex immunohistochemistry in 27 PT-metastasis pairs we retrospectively collected.

Results: Up to 64% of CRC metastases exhibited concordant CMS groups with matched PT, and the TME of metastases was similar to that of PT. For most common distant metastases, liver metastases were predominantly CMS2 and lung and peritoneal metastases were mainly CMS4, highlighting "seed" of tumor cells of different CMS groups had a preference for metastasis to "soil" of specific organs. Compared with PT, cancer-associated fibroblasts (CAF) reduced in liver metastases, CD4+T cells and M2-like macrophages increased in lung metastases, and M2-like macrophages and CAF increased in peritoneal metastases.

Conclusion: Our findings underscore the importance of CMS-guided specific organ monitoring and treatment post-primary tumor surgery for patients. Differences in immune-stromal infiltration among different metastases provide targeted therapeutic opportunities for metastatic CRC.

Keywords: colorectal cancer; consensus molecular subtypes; metastases; primary tumors; tumor microenvironment.

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (Grant no. 82173236), the Science and Technology Planning Project of Guangdong Province (Grant no. 202206080008), the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (Grant no. 2020B1111170004), Guangzhou High-level Key Clinical Specialty Construction Project (No.9), the Project of Key Medical Discipline in Guangzhou (2021–2023) and Guangzhou Science and Technology Planning Project (Grant no. 202206080008), Guangzhou Planned Project of Science and Technology (Grant no. 202102010024), Guangdong Basic and Applied Basic Research Foundation (Grant no. 2021B1515420004), the Science and Technology Projects in Guangzhou (Grant no. 202201020363).