Mechanisms and Models of Testis Specific Serine Kinase 6: A Novel Therapeutic Target in Colorectal Cancer - Tumors frequently re-activate genes whose expression is otherwise restricted to gametogenic tissues including the ovary, placenta and testes. Tumorigenic expression of these genes, known collectively as cancer-testes antigens (CTAs), has been documented for over 25 years, however functional knowledge of the contribution of these gene products to tumorigenesis remains scant. In our preliminary research, we have discovered that the CTA Testis-Specific Serine Kinase 6 (TSSK6) is expressed in more than 50% of colorectal cancer (CRC) cases. Importantly, elevated TSSK6 expression correlates with reduced relapse-free survival in CRC. Although TSSK6 is crucial for male fertility, knockout mice otherwise develop normally. These findings suggest that targeting TSSK6 could offer a wide therapeutic window if it is essential for tumorigenic behaviors. Indeed, initial studies have revealed that suppressing TSSK6 expression inhibits anchorage-independent growth, invasion, and in vivo growth of CRC. Conversely, introducing TSSK6 into non- transformed colonic epithelial cells or CRC cell lines lacking TSSK6 promotes these tumorigenic phenotypes. Notably, the oncogenic behavior of TSSK6 depends on its kinase activity. Additionally, TSSK6-expressing cells exhibit increased resistance to a range of therapeutics. Our initial data suggests that these phenotypes are mediated by signaling of TSSK6 at focal adhesions that enhances adherence and survival signaling. This proposal is centered on a a comprehensive investigation into TSSK6's influence on focal adhesion formation and signaling (Aim 1) and its influence of tumor metastases, viability and chemoresistance in mouse and organoid models. By achieving these aims, we will reveal a previously unknown signaling pathway, driven by the aberrant expression of a testes kinase, that facilitates the acquisition of invasive phenotypes in cancer. This work is expected to provide functional biomarkers and credible model systems essential for pursuing TSSK6 as a therapeutic target.
