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Abstract Prostate cancer (PC) is the leading type of cancer in men accounting for more than 25% of all newly reported cancer cases and remains the second leading cause of cancer-related deaths in men in USA in 2023. The success of early treatments has resulted in a 98% 5-year survival rate for early-stage PC. However, resistance to androgen ablation can lead to metastatic castration-resistant prostate cancer (mCRPC), with a significant drop in the survival rate to ~30%. The metastatic cascade involves changes in adhesive, metabolic and signaling properties of PC cells, allowing them to survive, proliferate and thrive in their new microenvironment. Kindlin-2 (K2), a cytoskeletal adapter protein, is highly expressed in cancer, including PC cells and tumors, contributing to their tumorigenic properties. The present study focuses on three K2 functions relevant to PC metastasis: 1) Reduction in K2 levels, achieved through CRISPR/Cas9, profoundly affected the tumorigenic properties of PC cell lines LNCaP (androgen dependent), DU145, and PC3 (both androgen independent), influencing colony formation, invasion, and adhesion to integrin ligands. While reduction in K2 was observed, K1 and K3 levels in these cell lines was not altered by K2KO. 2) The E3 ubiquitin ligase, Parkin, known for its role in Parkinson’s disease, has emerged as a tumor suppressor inhibiting various cancer hallmarks. Our recently published studies showed that Parkin induces ubiquitination of specific lysines in K2, leading to the hypothesis that Parkin acts as a tumor suppressor by targeting K2 for degradation. Stable over-expression of Parkin inhibited adhesion to fibrinogen (Fg), while loss of function Parkin mutants failed to do so, supporting a role of Parkin in K2 turnover and its impact on mitochondrial dynamics. We are currently investigating the effect of K2-lysines mutants as well as loss of function Parkin mutants on the progression and metastasis of PC tumors in vivo. 3) K2's established function is the regulation of integrin activation, affecting adhesion receptors' transition from low to high affinity/avidity states. The K2-integrin axis is pivotal for understanding oncogenic responses, and its role in the prostate microenvironment in PC progression and metastasis is under exploration using our newly established K2-floxed mouse. The K2-floxed mice are currently being crossed with mice harboring prostate-epithelial specific cre under control of the probasin (Pbsn) promoter. These animal studies will shed light on K2's contribution to PC development and progression in vivo, providing insights into its role in the prostate microenvironment. To sum up, this study emphasizes the crucial role of K2 in the tumorigenic properties of PC cells and tumors. By incorporating CRISPR/Cas9 and innovative mouse models, the study seeks to shed the lights on the mechanisms through which K2 contributes to PC development and progression. Citation Format: Lamyae El Khalki, Wei Wang, Neelum A. Yousaf Zai, Justin Szpendyk, Elzbieta Pluskota, Katarzyna Bialkowska, Edward F. Plow, Lucia R. Languino, Dario C. Altieri, Khalid Sossey-Alaoui. Role of kindlin-2 in prostate cancer progression and metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4380.
Khalki et al. (Fri,) studied this question.