Human colon cancer-derived Clostridioides difficile strains drive colonic tumorigenesis in mice

ARTICLE: Human colon cancer-derived Clostridioides difficile strains drive colonic tumorigenesis in mice

AUTHORS: Julia L Drewes, Jie Chen, Nicholas O Markham, Reece J Knippel, Jada C Domingue, Ada J Tam, June L Chan, Lana Kim, Madison McMann, Courtney Stevens, Christine M Dejea, Sarah Tomkovich, John Michel, James R White, Fuad Mohammad, Victoria L Campodonico, Cody N Heiser, Xinqun Wu, Shaoguang Wu, Hua Ding, Patricia Simner, Karen Carroll, Martha J Shrubsole, Robert A Anders, Seth T Walk, Christian Jobin, Fengyi Wan, Robert J Coffey, Franck Housseau, Ken S Lau, Cynthia L Sears

JOURNAL: Cancer Discov. 2022 Jun 9;candisc.1273.2021-10-4 15:58:09.930. doi: 10.1158/2159-8290.CD-21-1273. Online ahead of print.

Abstract

Defining the complex role of the microbiome in colorectal cancer (CRC) and the discovery of novel, pro-tumorigenic microbes are areas of active investigation. In the present study, culturing and reassociation experiments revealed that toxigenic strains of Clostridioides difficile drove the tumorigenic phenotype of a subset of CRC patient-derived mucosal slurries in germ-free ApcMin/+ mice. Tumorigenesis was dependent on the C. difficile toxin TcdB and was associated with induction of Wnt signaling, reactive oxygen species, and pro-tumorigenic mucosal immune responses marked by infiltration of activated myeloid cells and interleukin-17 (IL-17)-producing lymphoid and innate lymphoid cell subsets. These findings suggest that chronic colonization with toxigenic C. difficile is a potential driver of CRC in patients.

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