@article{cc8ab2acdfd64b23bc97628f56b964a8,
title = "Inhibition of HCK in myeloid cells restricts pancreatic tumor growth and metastasis",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a low 5-year survival rate and is associated with poor response to therapy. Elevated expression of the myeloid-specific hematopoietic cell kinase (HCK) is observed in PDAC and correlates with reduced patient survival. To determine whether aberrant HCK signaling in myeloid cells is involved in PDAC growth and metastasis, we established orthotopic and intrasplenic PDAC tumors in wild-type and HCK knockout mice. Genetic ablation of HCK impaired PDAC growth and metastasis by inducing an immune-stimulatory endotype in myeloid cells, which in turn reduced the desmoplastic microenvironment and enhanced cytotoxic effector cell infiltration. Consequently, genetic ablation or therapeutic inhibition of HCK minimized metastatic spread, enhanced the efficacy of chemotherapy, and overcame resistance to anti-PD1, anti-CTLA4, or stimulatory anti-CD40 immunotherapy. Our results provide strong rationale for HCK to be developed as a therapeutic target to improve the response of PDAC to chemo- and immunotherapy.",
keywords = "CP: Cancer, CP: Immunology, desmoplasia, drug resistance, hematopoietic cell kinase, immune suppression, immunotherapy, myeloid cells, pancreatic cancer, tumor microenvironment",
author = "Poh, {Ashleigh R.} and Megan O'Brien and David Chisanga and Hong He and David Baloyan and Jasmin Traichel and Christine Dijkstra and Micha{\"e}l Chopin and Stephen Nutt and Lachlan Whitehead and Louis Boon and Ashleigh Parkin and Clifford Lowell and Marina Pajic and Wei Shi and Mehrdad Nikfarjam and Matthias Ernst",
note = "Funding Information: This work was supported in parts through the Victorian State Government Operational Infrastructure Support and the National Health and Medical Research Council (NHMRC) of Australia project and development grants 1081373, 1092788, and 2014063. C.A.L. received funding from the UC Cancer Research Coordinating Committee (CRR-20-636450). M.E. received funding from Ludwig Cancer Research and is a NHMRC Investigator grant recipient (1173814). A.R.P. received support from 2018 Priority-driven Collaborative Cancer Research Scheme Grant (1157894) co-funded by Cancer Australia, Cure Cancer and Pancare Foundation; a Tour de Cure Early Career Seed Grant (RSP-060-18/19); and an Avner Collaboration Grant from PanKind, The Australian Pancreatic Cancer Foundation in collaboration with Tour de Cure and Woolworths Limited through Woolies on Wheels and Walks. A.R.P. is an NHMRC Peter Doherty Early Career Fellow (1166447). M.P. is supported by an NHMRC career development fellowship (1162556) and NHMRC project grant (1162860). We acknowledge The Collie Foundation for providing funds to purchase the Leica Aperio slide scanner. We also acknowledge the use of the services and facilities of the AGRF. Conception and design: A.R.P. and M.E.; development of methodology: A.R.P. W.S. M.N. and M.E.; acquisition of data: A.R.P. M.O.B. D.C. D.B. J.T. M.P. W.S. and M.E.; analysis and interpretation of data: A.R.P. M.O.B. D.C. D.B. J.T. M.P. W.S. M.N. and M.E.; writing, review, and/or revision of the manuscript: A.R.P. M.O.B. H.H. D.C. D.B. J.T. C.D. L.B. A.P. C.L. M.P. W.S. M.N. and M.E.; administrative, technical, or material support: A.R.P. M.O.B. H.H. D.C. D.B. J.T. M.C. S.N. C.D. L.W. L.B. A.P. C.L. M.P. W.S. M.N. and M.E.; study supervision: A.R.P. W.S. M.N. and M.E. A.R.P. and M.E. are inventors on a patent application related to this work filed by The Olivia Newton-John Cancer Research Institute (PCT/AU2021/051073) on the 16th of September 2021. We support inclusive, diverse, and equitable conduct of research. Funding Information: This work was supported in parts through the Victorian State Government Operational Infrastructure Support and the National Health and Medical Research Council ( NHMRC ) of Australia project and development grants 1081373 , 1092788 , and 2014063 . C.A.L. received funding from the UC Cancer Research Coordinating Committee ( CRR-20-636450 ). M.E. received funding from Ludwig Cancer Research and is a NHMRC Investigator grant recipient ( 1173814 ). A.R.P. received support from 2018 Priority-driven Collaborative Cancer Research Scheme Grant ( 1157894 ) co-funded by Cancer Australia, Cure Cancer and Pancare Foundation ; a Tour de Cure Early Career Seed Grant ( RSP-060-18/19 ); and an Avner Collaboration Grant from PanKind, The Australian Pancreatic Cancer Foundation in collaboration with Tour de Cure and Woolworths Limited through Woolies on Wheels and Walks. A.R.P. is an NHMRC Peter Doherty Early Career Fellow ( 1166447 ). M.P. is supported by an NHMRC career development fellowship ( 1162556 ) and NHMRC project grant ( 1162860 ). We acknowledge The Collie Foundation for providing funds to purchase the Leica Aperio slide scanner. We also acknowledge the use of the services and facilities of the AGRF. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = oct,
day = "11",
doi = "10.1016/j.celrep.2022.111479",
language = "English",
volume = "41",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "2",
}
