Abstract LB-133: Excessive activation of the Src-kinase HCK in the tumor stroma promotes progression of solid tumors

Abstract

Abstract Hemopoietic cell kinase, HCK, is a Src-family kinase expressed in myeloid and B-lymphoid cells, regulates innate immune cell functions, and is aberrantly activated and/or expressed (incl HCK gene amplification) in solid tumors of the colon, stomach, lung and other organs. Here we exploit the Hck(CA) mouse model, which carries a constitutively activating germline mutation and spontaneously develops pulmonary inflammation, airspace enlargement and cellular consolidation highly reminiscent of patient with chronic obstructive pulmonary disease, COPD [1]. To establish whether aberrant activation of endogenous Hck promotes tumorigenesis, we tested three established cancer models. First, we found lung adenocarcinoma burden in Hck(CA)x Kras(LSL-G12D) mice compared to Kras(LSL-G12D) mice, where the oncogenic KrasG12D transgene becomes activated in response to transnasal administration of adenovirus-encoded Cre recombinase. Second, using gp130(F/+) mice as a strain predisposed to the development of intestinal-type gastric cancer [2], we established that compound Hck(CA)x gp130(F/+), developed tumor burden similar to that of gp130(F/F) animals. Furthermore, tumors from Hck(CA)x gp130(F/+) mice, but not from gp130(F/F) mice, showed sub-mucosal invasion. Third, we modeled sporadic colorectal cancer by weekly administration of the alkylating agent azoxymethane for 6 consecutive weeks [3]. Compared to wild-type mice, Hck(CA) mice exhibited increased tumor frequency and multiplicity, and colonic tumors in Hck(CA) mice showed mucosal invasion, which was absent from tumors in wild-type mice. In all models the Hck(CA) allele increased tumor cell proliferation and associated Stat3, Erk, Akt and S6 cytoplasmic signaling, although the total number of tumor-associated macrophages remained unchanged by the presence of the Hck(CA) allele. However gene expression profiling of the latter cells revealed excessive alternative macrophage activation from Hck(CA) mice with prominent expression of Il4, Il10, Il13, Arg1 and Ym1. Accordingly, adoptive transfer of Hck(CA) bone-marrow was sufficient to confer increase tumor burden and promote alternative macrophage polarisation, while reconstitution with triple Hck(KO)x Fgr(KO)x Lyn(KO) bone marrow reduced tumor burden. Collectively, our data suggest that mutations affecting the stroma, and macrophage polarization specifically, confer tumor progression and that HCK may provide a novel target for rational cancer drug development. References 1) J. Exp. Med. 196:589-604 (2002) 2) Nat Med 11:845 (2005) 3) Cancer Cell 24:25 (2013) Citation Format: Robert O'Donoghue, Ashleigh Poh, Adele Preaudet, Matthias Ernst. Excessive activation of the Src-kinase HCK in the tumor stroma promotes progression of solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-133. doi:10.1158/1538-7445.AM2015-LB-133