Microenvironmental changes in familial adenomatous polyposis during colorectal cancer carcinogenesis

Kyoko Hisano, Yusuke Mizuuchi, Kenoki Ohuchida, Jun Kawata, Nobuhiro Torata, Jinghui Zhang, Naoki Katayama, Chikanori Tsutsumi, Shoichi Nakamura, Sho Okuda, Yoshiki Otsubo, Koji Tamura, Kinuko Nagayoshi, Naoki Ikenaga, Koji Shindo, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura

Research output: Contribution to journalArticlepeer-review

Abstract

Familial adenomatous polyposis (FAP) is a heritable disease that increases the risk of colorectal cancer (CRC) development because of heterozygous mutations in APC. Little is known about the microenvironment of FAP. Here, single-cell RNA sequencing was performed on matched normal tissues, adenomas, and carcinomas from four patients with FAP. We analyzed the transcriptomes of 56,225 unsorted single cells, revealing the heterogeneity of each cell type, and compared gene expression among tissues. Then we compared the gene expression with that of sporadic CRC. Furthermore, we analyzed specimens of 26 FAP patients and 40 sporadic CRC patients by immunohistochemistry. Immunosuppressiveness of myeloid cells, fibroblasts, and regulatory T cells was upregulated even in the early stages of carcinogenesis. CD8+ T cells became exhausted only in carcinoma, although the cytotoxicity of CD8+ T cells was gradually increased according to the carcinogenic step. When compared with those in the sporadic CRC microenvironment, the composition and function of each cell type in the FAP-derived CRC microenvironment had differences. Our findings indicate that an immunosuppressive microenvironment is constructed from a precancerous stage in FAP.

Original languageEnglish
Article number216822
JournalCancer Letters
Volume589
DOIs
Publication statusPublished - May 1 2024

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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