Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression.

Autor: Churchhouse AMD; Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK., Billard CV; Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK., Suzuki T; Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK.; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Pohl SÖG; Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK., Doleschall NJ; Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK., Donnelly K; Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK., Nixon C; Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK., Arends MJ; Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK., Din S; Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK., Kirkwood K; Department of Pathology, Western General Hospital, Edinburgh, UK., Marques Junior J; Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK., Von Kriegsheim A; Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK., Coffelt SB; Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK.; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Myant KB; Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK. Kevin.myant@ed.ac.uk.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 Oct; Vol. 43 (42), pp. 3094-3107. Date of Electronic Publication: 2024 Sep 07.
DOI: 10.1038/s41388-024-03135-9
Abstrakt: Inflammatory Bowel Disease-associated colorectal cancer (IBD-CRC) is a known and serious complication of Inflammatory Bowel Disease (IBD) affecting the colon. However, relatively little is known about the pathogenesis of IBD-associated colorectal cancer in comparison with its sporadic cancer counterpart. Here, we investigated the function of Dock2, a gene mutated in ~10% of IBD-associated colorectal cancers that encodes a guanine nucleotide exchange factor (GEF). Using a genetically engineered mouse model of IBD-CRC, we found that whole body loss of Dock2 increases tumourigenesis via immune dysregulation. Dock2-deficient tumours displayed increased levels of IFNγ-associated genes, including the tryptophan metabolising, immune modulatory enzyme, IDO1, when compared to Dock2-proficient tumours. This phenotype was driven by increased IFNγ-production in T cell populations, which infiltrated Dock2-deficient tumours, promoting IDO1 expression in tumour epithelial cells. We show that IDO1 inhibition delays tumourigenesis in Dock2 knockout mice, and we confirm that this pathway is conserved across species as IDO1 expression is elevated in human IBD-CRC and in sporadic CRC cases with mutated DOCK2. Together, these data demonstrate a previously unidentified tumour suppressive role of DOCK2 that limits IFNγ-induced IDO1 expression and cancer progression, opening potential new avenues for therapeutic intervention.
(© 2024. The Author(s).)
Databáze: MEDLINE
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