Journal article

Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice

Ashleigh R Poh, Amy R Dwyer, Moritz F Eissmann, Ashwini L Chand, David Baloyan, Louis Boon, Michael W Murrey, Lachlan Whitehead, Megan O'Brien, Clifford A Lowell, Tracy L Putoczki, Fiona J Pixley, Robert JJ O'Donoghue, Matthias Ernst

CANCER IMMUNOLOGY RESEARCH | AMER ASSOC CANCER RESEARCH | Published : 2020

Abstract

Persistent activation of the latent transcription factor STAT3 is observed in gastric tumor epithelial and immune cells and is associated with a poor patient prognosis. Although targeting STAT3-activating upstream kinases offers therapeutically viable targets with limited specificity, direct inhibition of STAT3 remains challenging. Here we provide functional evidence that myeloid-specific hematopoietic cell kinase (HCK) activity can drive STAT3-dependent epithelial tumor growth in mice and is associated with alternative macrophage activation alongside matrix remodeling and tumor cell invasion. Accordingly, genetic reduction of HCK expression in bone marrow-derived cells or systemic pharmacol..

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Grants

Awarded by National Health and Medical Research Council (NHMRC) of Australia


Awarded by Debbie's Dream Foundation-Stupid Strong-AACR Gastric Cancer Research Fellowship, in memory of Candace Netzer


Awarded by Victoria Cancer Agency Early Career Seed Grant


Funding Acknowledgements

This work was made possible through the Victorian State Government Operational Infrastructure Support; the National Health and Medical Research Council (NHMRC) of Australia project grants 1025239, 1079257, 1081373, and 1092788; and the RFA-UD from La Trobe University. M. Ernst also received funding from Ludwig Cancer Research. A.R. Poh received funding from an Australian PostGraduate Award PhD Scholarship and the Cancer Therapeutics CTx PhD Top-Up Scholarship. Research supported by the 2018 Debbie's Dream Foundation-Stupid Strong-AACR Gastric Cancer Research Fellowship, in memory of Candace Netzer, Grant Number 18-40-41-POH. A. R. Dwyer received funding from an Australian Post-Graduate Award PhD Scholarship and University of Western Australia PhD Top-Up Scholarship. R. J.J. O'Donoghue received funding from a Victoria Cancer Agency Early Career Seed Grant ESG13041. T.L. Putoczki is a Victorian Cancer Agency Fellow. M. Ernst and A.R. Poh are Research Fellows of the NHMRC.