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

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 pharmacologic inhibition of HCK activity suppresses alternative macrophage polarization and epithelial STAT3 activation, and impairs tumor growth. These data validate HCK as a molecular target for the treatment of human solid tumors harboring excessive STAT3 activity.

HCK promotes glioblastoma progression by TGFβ signaling

“…In the present study, HCK was demonstrated to be highly expressed in both tumor tissues from patients with GBM and GBM cell lines. Previous studies also reported excessive HCK expression in colorectal, breast, and gastric cancer [11][12][13]. Subsequently, we analyzed the effects of HCK on GBM development both in vitro and in vivo.…”

“…The HCK, a member of SFKs, is expressed in hematopoietic system, primarily including cells of the myeloid and B lymphocyte lineages [9,10]. Excessive activation of HCK is associated with various leukemia, such as CML, multiple myeloma, and acute lymphoblastic leukemia, as well as solid malignancies including colorectal, breast, and gastric cancer [11][12][13]. Nevertheless, the roles of HCK in GBM remain to be examined.…”

“…The expression of HCK is limited to the hematopoietic system, primarily including cells of the myeloid and B lymphocyte lineages [9,10]. Excessive activation of HCK is reported to be associated with various leukemia, such as chronic myeloid leukemia (CML), multiple myeloma, and acute lymphoblastic leukemia, as well as solid malignancies including colorectal, breast, and gastric cancer [11][12][13]. In CML, HCK is activated by BCR/ABL, an oncogenic fusion protein in a large majority of CML as well as in some acute lymphocytic leukemia, leading to the persistent activation of STAT5 and its excessive accumulation in the cytoplasm, where STAT5 activates AKT through combining with PI3K and the adaptor protein GAB2, promoting cell growth and survival [14,15].…”

“…Furthermore, HCK is also associated with inflammatory signaling. It is involved in CD14/Toll-like receptor (TLR) 4 cell signaling, and regulates the production of TNF-a, IL-1, and IL-6 stimulated by lipopolysaccharide, resulting in inflammation perpetuation and neoplastic transformation sustentation in tumor cell [13,14].…”

­­Prognostic analysis of tumor mutation burden combined with immune infiltration of Thymic epithelial tumors

“…It has been reported that, excessive activation of HCK is associated with various leukemias, such as chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia, as well as solid malignancies including colorectal cancer, breast cancer and gastric cancer. In gastric tumor epithelial cells, over expression of HCK can induce alternative polarization of macrophages, activation of STAT3 and promote tumor growth [26]. Roseweir et al [27] reported that, HCK was highly expressed in patients with colorectal cancer, it could promote tumor progression, inhibit local lymphocyte in ammatory in ltration and are related to the poor prognosis of patients.…”