Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

Abstract

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.

People
Churchhouse, Antonia M.D.
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

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Billard, Caroline V.
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

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Suzuki, Toshiyasu
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

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Pohl, Sebastian O.G.
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

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Donnelly, Kevin
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

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Nixon, Colin
Author

Elbassioni, Ali Ali Mohamed and Raheem, Anmar A. and Song, Jian and Johnston, Alexander S. and Trivett, Cara and Lin, Hong and Zhang, Haobo and Bradley, Ashley and Higgins, Erin and Mooney, Leanne and Koay, Yen Chin and O'Toole, Dylan and Herzyk, Pawel and Nixon, Colin and Blyth, Karen and O'Sullivan, John F. and Lang, Ninian N. and Berry, Colin and Braun, Thomas and Schiattarella, Gabriele G. and Giacca, Mauro and McBride, Martin W. and Nicklin, Stuart A. and Cameron, Ewan R. and Loughrey, Christopher M. and MacDonald, Eilidh A. (2025) Targeting Runx1 protects against heart failure with preserved ejection fraction. bioRxiv.

Pennel, Kathryn and Kurniawan, Ahmad and Al-Badran, Sara Samir Foad and Schubert Santana, Leonor and Quinn, Jean and Nixon, Colin and Hatthakarnkul, Phimmada and Maka, Noori and Roxburgh, Campbell and McMillan, Donald and Edwards, Joanne (2024) IL6 and IL6R as prognostic biomarkers in colorectal cancer. Biomolecules, 14 (12): 1629. ISSN 2218-273X

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

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Arends, Mark J.
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

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Din, Shahida
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

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Kirkwood, Kathryn
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

See full publications list
Marques Junior, Jair
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

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Von Kriegsheim, Alexander
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

See full publications list
Coffelt, Seth B.
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

Kumar, Saumya and Basto, Afonso P. and Ribeiro, Filipa and Almeida, Silvia C.P. and Campos, Patricia and Peres, Carina and Pulvirenti, Nadia and Al-Khalidi, Sarwah and Kilbey, Anna and Tosello, Jimena and Piaggio, Eliane and Russo, Momtchilo and Gama-Carvalho, Margarida and Coffelt, Seth B. and Roberts, Ed W. and Geginat, Jens and Florindo, Helena F. and Graca, Luis (2024) Specialized Tfh cell subsets driving type-1 and type-21 humoral responses in lymphoid tissue. Cell Discovery, 10: 64. ISSN 2056-5968

Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723

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Myant, Kevin B.
Author

Churchhouse, Antonia M.D. and Billard, Caroline V. and Suzuki, Toshiyasu and Pohl, Sebastian O.G. and Donnelly, Kevin and Nixon, Colin and Arends, Mark J. and Din, Shahida and Kirkwood, Kathryn and Marques Junior, Jair and Von Kriegsheim, Alexander and Coffelt, Seth B. and Myant, Kevin B. (2024) Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene, 43 (42). pp. 3094-3107. ISSN 0950-9232

See full publications list
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