Activation of the myeloid-specific Src-family kinase Hematopoietic Cell Kinase (HCK) promotes proliferation and survival of immune cells, and triggers hematological malignancies as a tumor cell-intrinsic oncogene. However, the role of HCK in the tumor stroma of solid cancers remains unexplored.
We analyzed the expression level of HCK in matched biopsies from sporadic colorectal cancer patients and observed elevated HCK phosphorylation in a subset of tumors compared to unaffected colons. Analysis of corresponding RNAseq data revealed a striking correlation between tumors with high HCK gene expression and a gene signature of tumor-promoting alternatively-activated macrophages. To functionally assess this observation, we subjected HckCA mice that express a constitutively active form of the kinase (HckCA) to a chemically-induced model of sporadic colorectal cancer. HckCA mice developed twice as many tumors that were also significantly larger to wild-type animals, and this was associated with a significant increase in alternatively-activated macrophages in tumors of HckCA mice. Likewise, adoptive bone-marrow transfer experiments enhanced tumor formation and alternative macrophage differentiation in WT mice reconstituted with HckCA bone-marrow, with a reciprocal decrease of these parameters in HckCA mice reconstituted with WT bone-marrow. Accordingly, genetic and pharmacological inhibition of Hck activity suppressed alternative macrophage polarization and the growth of colorectal cancer xenografts.
Together, our findings suggest that increased Hck activity in the tumor stroma promotes the progression of solid cancers by modulating the phenotype of tumor-associated myeloid cells. Thus, Hck represents a rational therapeutic target for macrophage re-education in solid cancers by limiting polarization of tumor-promoting alternatively-activated macrophages.