NLN Depletion Enhances WNT3A Secretion and Therapy Resistance in mCRPC via KIF11-Mediated Cellular Trafficking

WNT signalling, an integral orchestrator in an assortment of developmental and pathological pathways, exhibits aberrant regulation in a variety of human malignancies, encompassing prostate cancer (PCa). Particularly, in metastatic castration-resistant prostate cancer (mCRPC), WNT signalling demonstrates dysregulated activity, albeit the precise molecular underpinnings of this ectopic signalling remain predominantly undefined. Within this investigation, we illuminate the role of the previously unidentified tumor suppressor, NLN, which serves as a molecular scaffold to facilitate KIF11 aggregation. A notable depletion of NLN was observed in approximately 30% of mCRPC cases, a deficiency that catalyzes the unleashing of KIF11-dependent cellular translocation of WNT3A, culminating in amplified WNT3A secretion into the tumor microenvironment (TME). This excessive extracellular WNT3A release augments the adaptive resilience of proximal mCRPC cells, fostering resistance against the prevailing standard-of-care AR-targeted therapies. The findings from this study delineate a hitherto uncharacterized, cancer cell-autonomous mechanism that modifies the TME via modulated WNT secretion, thereby inciting resistance to AR-targeted therapies. Moreover, these results underscore the potential clinical utility of NLN level assessments as a prognostic biomarker for mCRPC, and propose the potential efficacy of WNT3A inhibitors as a therapeutic approach to counteract resistance.