{"id":"doi:10.1016/j.ccell.2022.01.004","kind":"article","title":"Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer","authors":["Nicolas AM","Pesic M","Engel E","Ziegler PK","Diefenhardt M","Kennel KB","Buettner F","Conche C","Petrocelli V","Elwakeel E","Weigert A","Zinoveva A","Fleischmann M","Häupl B","Karakütük C","Bohnenberger H","Mosa MH","Kaderali L","Gaedcke J","Ghadimi M","Rödel F","Arkan MC","Oellerich T","Rödel C","Fokas E"],"author_count":26,"year":2022,"published":"2022-02-03","venue":"Cancer cell","cited_by":306,"doi":"10.1016/j.ccell.2022.01.004","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.ccell.2022.01.004","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.ccell.2022.01.004","updated":null,"pmid":"35120600","pmcid":null,"openalex_id":null,"pdf_url":null,"abstract":"Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression. Consistently, IL-1 inhibition, prevention of iCAFs senescence, or senolytic therapy sensitizes mice to irradiation, while lower IL-1 receptor antagonist serum levels in rectal patients correlate with poor prognosis. Collectively, we unravel a critical role for iCAFs in rectal cancer therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of cancer-associated fibroblasts senescence.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":false,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer\" by Nicolas AM, Pesic M, Engel E et al., https://doi.org/10.1016/j.ccell.2022.01.004, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"aging-longevity","name":"Biology of Aging & Longevity","domain_slug":"medicine"}],"cited_in_dossiers":[]}