Microbiome Dysbiosis, Neutrophil Recruitment and Mesenchymal Transition of Mesothelial Cells Promotes Peritoneal Metastasis of Colorectal Cancer

Overview

Journal Nat Cancer

Specialty Oncology

Date 2025 Feb 18

PMID 39966610

Authors

Qingguo Li

Yiwei Xiao

Lingyu Han

Wenqin Luo

Weixing Dai

Hongsheng Fang

Renjie Wang

Ye Xu

Sanjun Cai

Ajay Goel

Fan Bai

Guoxiang Cai

Affiliations

Soon will be listed here.

Abstract

Peritoneal metastasis (PM) is common in colorectal cancer (CRC), yet its underlying mechanisms are poorly understood. Here, we explored the transcriptional profile of CRC, PM and adjacent tissues revealing key players that facilitate PM. Single-cell analysis of 48 matched samples from 12 patients revealed that remodeling of malignant cells and the tumor microenvironment promotes CRC progression and metastasis. Multiplexed imaging confirmed depletion in PM by enrichment in CRC tissues of neutrophils associated with mucosal immunity disruption, intestinal microbiota dysbiosis and mesenchymal transition of both cancerous and mesothelial cells. Functional analyses in cell lines, organoids and in vivo models demonstrated that dysbiosis promoted inflammation and protumor neutrophil recruitment, while coupled mesenchymal transition of malignant and mesothelial cells disrupted the stromal structure and increased cancer cell invasiveness. Our findings suggest that targeting mesothelial cells and tumor microenvironment remodeling may offer therapeutic strategies for CRC-PM.

References

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Biller L, Schrag D . Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA. 2021; 325(7):669-685. DOI: 10.1001/jama.2021.0106. View

Segelman J, Granath F, Holm T, Machado M, Mahteme H, Martling A . Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer. Br J Surg. 2012; 99(5):699-705. DOI: 10.1002/bjs.8679. View

Enblad M, Graf W, Birgisson H . Risk factors for appendiceal and colorectal peritoneal metastases. Eur J Surg Oncol. 2018; 44(7):997-1005. DOI: 10.1016/j.ejso.2018.02.245. View

van Gestel Y, Thomassen I, Lemmens V, Pruijt J, van Herk-Sukel M, Rutten H . Metachronous peritoneal carcinomatosis after curative treatment of colorectal cancer. Eur J Surg Oncol. 2013; 40(8):963-9. DOI: 10.1016/j.ejso.2013.10.001. View

Kranenburg O, van Der Speeten K, de Hingh I . Peritoneal Metastases From Colorectal Cancer: Defining and Addressing the Challenges. Front Oncol. 2021; 11:650098. PMC: 8010649. DOI: 10.3389/fonc.2021.650098. View

Klaver C, Groenen H, Morton D, Laurberg S, Bemelman W, Tanis P . Recommendations and consensus on the treatment of peritoneal metastases of colorectal origin: a systematic review of national and international guidelines. Colorectal Dis. 2016; 19(3):224-236. DOI: 10.1111/codi.13593. View

Elias D, Lefevre J, Chevalier J, Brouquet A, Marchal F, Classe J . Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol. 2008; 27(5):681-5. DOI: 10.1200/JCO.2008.19.7160. View

Sluiter N, Rovers K, Salhi Y, Vlek S, Coupe V, Verheul H . Metachronous Peritoneal Metastases After Adjuvant Chemotherapy are Associated with Poor Outcome After Cytoreduction and HIPEC. Ann Surg Oncol. 2018; 25(8):2347-2356. PMC: 6028868. DOI: 10.1245/s10434-018-6539-x. View

10.

Lenos K, Bach S, Moreno L, Ten Hoorn S, Sluiter N, Bootsma S . Molecular characterization of colorectal cancer related peritoneal metastatic disease. Nat Commun. 2022; 13(1):4443. PMC: 9352687. DOI: 10.1038/s41467-022-32198-z. View

11.

Chen B, Scurrah C, McKinley E, Simmons A, Ramirez-Solano M, Zhu X . Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps. Cell. 2021; 184(26):6262-6280.e26. PMC: 8941949. DOI: 10.1016/j.cell.2021.11.031. View

12.

Liu Y, Zhang Q, Xing B, Luo N, Gao R, Yu K . Immune phenotypic linkage between colorectal cancer and liver metastasis. Cancer Cell. 2022; 40(4):424-437.e5. DOI: 10.1016/j.ccell.2022.02.013. View

13.

Pelka K, Hofree M, Chen J, Sarkizova S, Pirl J, Jorgji V . Spatially organized multicellular immune hubs in human colorectal cancer. Cell. 2021; 184(18):4734-4752.e20. PMC: 8772395. DOI: 10.1016/j.cell.2021.08.003. View

14.

Zhang L, Li Z, Skrzypczynska K, Fang Q, Zhang W, OBrien S . Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer. Cell. 2020; 181(2):442-459.e29. DOI: 10.1016/j.cell.2020.03.048. View

15.

Zhang L, Yu X, Zheng L, Zhang Y, Li Y, Fang Q . Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. Nature. 2018; 564(7735):268-272. DOI: 10.1038/s41586-018-0694-x. View

16.

Lee H, Hong Y, Etlioglu H, Cho Y, Pomella V, Van den Bosch B . Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer. Nat Genet. 2020; 52(6):594-603. DOI: 10.1038/s41588-020-0636-z. View

17.

Kienes I, Johnston E, Bitto N, Kaparakis-Liaskos M, Kufer T . Bacterial subversion of NLR-mediated immune responses. Front Immunol. 2022; 13:930882. PMC: 9367220. DOI: 10.3389/fimmu.2022.930882. View

18.

Brubaker S, Bonham K, Zanoni I, Kagan J . Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol. 2015; 33:257-90. PMC: 5146691. DOI: 10.1146/annurev-immunol-032414-112240. View

19.

Galeano Nino J, Wu H, LaCourse K, Kempchinsky A, Baryiames A, Barber B . Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature. 2022; 611(7937):810-817. PMC: 9684076. DOI: 10.1038/s41586-022-05435-0. View

20.

Chen K, Magri G, Grasset E, Cerutti A . Rethinking mucosal antibody responses: IgM, IgG and IgD join IgA. Nat Rev Immunol. 2020; 20(7):427-441. PMC: 10262260. DOI: 10.1038/s41577-019-0261-1. View