title: Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression.
abstract: Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies.
authors.affiliation: Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Ashleigh R
authors.initials: AR
authors.lastname: Poh
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Love
authors.affiliation: Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia.
authors.forename: Frederick
authors.initials: F
authors.lastname: Masson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Adele
authors.initials: A
authors.lastname: Preaudet
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Cary
authors.initials: C
authors.lastname: Tsui
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Lachlan
authors.initials: L
authors.lastname: Whitehead
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Monard
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Khakham
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Lotta
authors.initials: L
authors.lastname: Burstroem
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lessene
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Colorectal Surgery, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia; School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sieber
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA 94143, USA.
authors.forename: Clifford
authors.initials: C
authors.lastname: Lowell
authors.affiliation: Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Putoczki
authors.affiliation: Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: robert.odonoghue@onjcri.org.au.
authors.forename: Robert J J
authors.initials: RJJ
authors.lastname: O'Donoghue
authors.affiliation: Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: matthias.ernst@onjcri.org.au.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008262:Macrophage Activation / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051572:Proto-Oncogene Proteins c-hck / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D011743:Pyrimidines; D011758:Pyrroles; C000620711:RK-20449; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C496631:HCK protein, human; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck
keywords: SRC family kinases; alternative macrophage polarization; colitis-associated colon cancer; colorectal cancer; hematopoietic cell kinase; mouse model; stat3; tumor microenvironment; tyrosine kinase inhibitor; xenograft