@article{16c88e23f664458982a19f4af557d6d2,
title = "Human Colon Cancer–Derived Clostridioides difficile Strains Drive Colonic Tumorigenesis in Mice",
abstract = "Defining the complex role of the microbiome in colorectal cancer and the discovery of novel, protumorigenic microbes are areas of active investigation. In the present study, culturing and reassociation experiments revealed that toxigenic strains of Clostridioides diffi-cile drove the tumorigenic phenotype of a subset of colorectal cancer 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 protumorigenic mucosal immune responses marked by the infiltration of activated myeloid cells and IL17-producing lymphoid and innate lymphoid cell subsets. These findings suggest that chronic colonization with toxigenic C. difficile is a potential driver of colorectal cancer in patients. SIGNIFICANCE: Colorectal cancer is a leading cause of cancer and cancer-related deaths worldwide, with a multifactorial etiology that likely includes procarcinogenic bacteria. Using human colon cancer specimens, culturing, and murine models, we demonstrate that chronic infection with the enteric patho-gen C. difficile is a previously unrecognized contributor to colonic tumorigenesis.",
author = "Drewes, {Julia L.} and Jie Chen and Markham, {Nicholas O.} and Knippel, {Reece J.} and Domingue, {Jada C.} and Tam, {Ada J.} and Chan, {June L.} and Lana Kim and Madison McMann and Courtney Stevens and Dejea, {Christine M.} and Sarah Tomkovich and John Michel and White, {James R.} and Fuad Mohammad and Campod{\'o}nico, {Victoria L.} and Heiser, {Cody N.} and Xinqun Wu and Shaoguang Wu and Hua Ding and Patricia Simner and Karen Carroll and Shrubsole, {Martha J.} and Anders, {Robert A.} and Walk, {Seth T.} and Christian Jobin and Fengyi Wan and Coffey, {Robert J.} and Franck Housseau and Lau, {Ken S.} and Sears, {Cynthia L.}",
note = "Funding Information: Isogenic toxin mutants of C. difficile strains 630∆erm and M7404 were constructed by the laboratory of Dr. Dena Lyras (Monash University in Australia). These strains were generously provided by Dr. Borden Lacy at Vanderbilt University with Dr. Lyras{\textquoteright} kind permission. We also acknowledge two summer students, Aishwarya Shet- tigar and Rebecca Gellman, for their efforts in helping to isolate the CIm_2663_3728T C. difficile strain, Dr. Henry Wood (Leeds, UK) for his input, and Bob Chen and Molly Bingham for their assistance in the scRNA-seq analyses. Mouse diagrams were created with BioRender. This study was supported by NIH grant R01CA196845 (C.L. Sears), NIH grant R00CA230192 (J.L. Drewes), NIH grant U2CCA233291 (M.J. Shrubsole, R.J. Coffey, K.S. Lau, C.L. Sears, J.L. Drewes, and N.O. Markham), NIH grant R01CA203891 (F. Housseau), NIH grant R01DK103831 (K.S. Lau), NIH grant P50CA236733 (R.J. Coffey and K.S. Lau), NIH grant R35CA197570 (R.J. Coffey), the Bloomberg– Kimmel Institute for Immunotherapy (C.L. Sears), a Cancer Grand Challenges OPTIMISTICC team grant (A27140) funded by Cancer Research UK (C.L. Sears), Johns Hopkins University Department of Medicine (C.L. Sears), Johns Hopkins University Sidney Kim-mel Cancer Center Core (C.L. Sears and F. Housseau), NIH grant P30DK089502 (Johns Hopkins University Conte Digestive Diseases Basic and Translational Research Core), NIH grant S10OD016374 (Johns Hopkins Microscope Facility Core), NIH grant T32 GM136577 (J. Michel), NIH grant R01DK073338 (C. Jobin), and Department of Veterans Affairs grant BX005699-01 (N.O. Markham). Funding Information: reports grants and personal fees from Bristol Myers Squibb and personal fees from AstraZeneca, Merck Sharp & Dohme, and Rapt Therapeutics during the conduct of the study. K.S. Lau reports grants from the NCI and the National Institute of Diabetes and Digestive and Kidney Diseases during the conduct of the study. C.L. Sears reports grants from the NCI (R01CA196845), the Bloomberg– Kimmel Institute for Immunotherapy, Cancer Research UK, Johns Hopkins University Department of Medicine, Johns Hopkins University Sidney Kimmel Cancer Center Core Grant, and the NIH (P30DK089502 and S10OD016374) during the conduct of the study, as well as grants from Janssen and Bristol Myers Squibb, and personal fees from Ferring and UpToDate outside the submitted work. No disclosures were reported by the other authors. Funding Information: N.O. Markham reports grants from the Department of Veterans Affairs during the conduct of the study. J.C. Domingue reports personal fees from AstraZeneca outside the submitted work. S. Tomkovich reports other support from Seres Therapeutics outside the submitted work. J.R. White reports other support from Resphera Biosciences LLC outside the submitted work. P. Simner reports grants and personal fees from BD Diagnostics, OpGen Inc., Shionogi Inc., and GeneCapture, grants from Affinity Biosensors and Qiagen, and nonfinancial support from Ares Genetics, CosmosID, and IDbyDNA outside the submitted work. K. Carroll reports grants from Meridian Diagnostics, Inc., Tufts University, and BD Diagnostics, Inc., and personal fees from Roche Molecular, Inc. and Thermo Fisher outside the submitted work. R.A. Anders Funding Information: Isogenic toxin mutants of C. difficile strains 630∆erm and M7404 were constructed by the laboratory of Dr. Dena Lyras (Monash University in Australia). These strains were generously provided by Dr. Borden Lacy at Vanderbilt University with Dr. Lyras{\textquoteright} kind permis-sion. We also acknowledge two summer students, Aishwarya Shet- tigar and Rebecca Gellman, for their efforts in helping to isolate the CIm_2663_3728T C. difficile strain, Dr. Henry Wood (Leeds, UK) for his input, and Bob Chen and Molly Bingham for their assistance in the scRNA-seq analyses. Mouse diagrams were created with BioRender. This study was supported by NIH grant R01CA196845 (C.L. Sears), NIH grant R00CA230192 (J.L. Drewes), NIH grant U2CCA233291 (M.J. Shrubsole, R.J. Coffey, K.S. Lau, C.L. Sears, J.L. Drewes, and N.O. Markham), NIH grant R01CA203891 (F. Housseau), NIH grant R01DK103831 (K.S. Lau), NIH grant P50CA236733 (R.J. Coffey and K.S. Lau), NIH grant R35CA197570 (R.J. Coffey), the Bloomberg– Kimmel Institute for Immunotherapy (C.L. Sears), a Cancer Grand Challenges OPTIMISTICC team grant (A27140) funded by Cancer Research UK (C.L. Sears), Johns Hopkins University Department of Medicine (C.L. Sears), Johns Hopkins University Sidney Kim-mel Cancer Center Core (C.L. Sears and F. Housseau), NIH grant P30DK089502 (Johns Hopkins University Conte Digestive Diseases Basic and Translational Research Core), NIH grant S10OD016374 (Johns Hopkins Microscope Facility Core), NIH grant T32 GM136577 (J. Michel), NIH grant R01DK073338 (C. Jobin), and Department of Veterans Affairs grant BX005699-01 (N.O. Markham). Note. Publisher Copyright: {\textcopyright} 2022 The Authors; Published by the American Association for Cancer Research.",
year = "2022",
month = aug,
day = "1",
doi = "10.1158/2159-8290.CD-21-1273",
language = "English (US)",
volume = "12",
pages = "1873--1885",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "8",
}