Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression.

2017-04-10

Poh, Ashleigh R

Love, Christopher G

Masson, Frederic

Preaudet, Adele

Tsui, Cary

Whitehead, Lachlan

Monard, Simon

Khakham, Yelena

Burstroem, Lotta

Lessene, Guillaume

Sieber, Oliver

Lowell, Clifford

Putoczki, Tracy L

O'Donoghue, Robert J J

Ernst, Matthias

SRC family kinases

Alternative macrophage polarization

Colitis-associated colon cancer

Colorectal cancer

Hematopoietic cell kinase

Mouse model

stat3

tumor microenvironment

tyrosine kinase inhibitor

xenograft

Journal Article

10.1016/j.ccell.2017.03.006

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.

link

Cancer cell 2017; 31(4): 563-575.e5

Cancer cell