Poster Presentation 28th Lorne Cancer Conference 2016

Excessive HCK Kinase Activity in the Tumour Stroma Promotes Colorectal Cancer Progression (#234)

Ashleigh R Poh 1 , Chris Love 1 , Guillaume Lessene 1 , Frederic Masson 1 2 , Tracy Putoczki 1 , Robert ODonoghue 1 2 , Matthias Ernst 1 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Olivia Newton John Cancer Research Institute, Heidelberg, Victoria

Increased activation of the myeloid-specific Hematopoietic Cell Kinase (HCK) is associated with a decreased prognosis in leukemia and has been shown to act as a tumour intrinsic oncogene by enhancing the proliferation and survival of hematopoietic immune cells. However, the role of HCK in solid malignancies remains unexplored. To address this, we analyzed the expression level of HCK in matched biopsies from sporadic colorectal cancer patients and observed elevated HCK activity in more than half of tumours compared to unaffected colons. RNAseq analysis of the corresponding biopsies also revealed an expression signature enriched for genes associated with the differentiation of pro-tumourigenic alternatively-activated macrophages in HCKHigh expressing tumours.

          To functionally assess the role of HCK signaling in colorectal cancer, HCK mutant mice that express a constitutively active form of the kinase (HCKCA) were subjected to a chemically-induced model of sporadic colorectal cancer. HCKCA mice developed larger and more frequent tumours compared to wild-type (WT) animals, coinciding with a significant increase in tumour-associated alternatively-activated macrophages. Furthermore, reciprocal adoptive bone-marrow transfers between HCKCA and WT mice showed enhanced tumour formation and alternative macrophage polarisation in HCKCA→WT mice, while these parameters were reduced in WT→HCKCA mice. Analysis of compound HCKCA;Rag1KO mice also demonstrated that excessive HCK activation in the tumour stroma could promote tumourigenesis and the polarisation of alternatively-activated macrophages independently of lymphocytes. Finally, pharmacologic targeting of HCK with a small molecule kinase inhibitor significantly reduced tumour development and impaired alternative macrophage polarisation.

Collectively, these findings suggest a role for HCK as a tumour extrinsic promoter in solid cancers by modulating the phenotype of tumour-associated immune cells. Furthermore, HCK represents a rational therapeutic target for solid cancers by limiting the capacity of alternative macrophage activation.