Abstract 6417: Prostate cancer exploits neurolysin to modulate the tumor microenvironment and therapy resistance via KIF11-mediated WNT secretion

Abstract The rapid emergence of resistance to targeted therapies poses a substantial challenge in managing various advanced cancers, including prostate cancer (PCa). The extent to which PCa cells can autonomously manipulate the tumor microenvironment (TME) and swiftly adapt to therapeutic challenges remains inadequately understood. We have elucidated that PCa cells can exploit neurolysin, a crucial regulator of neuronal signaling, to counter therapeutic interventions. The frequent absence of neurolysin results in increased WNT3A secretion into the TME and activates aberrant WNT signaling in adjacent cancer cells, thereby conferring AR targeted therapy resistance. This escalated WNT secretion and subsequent resistance are dependent on dysregulated cellular trafficking governed by the motor protein KIF11, which can be abolished by targeting either WNT3A or KIF11. These findings reveal an uncharted mechanism where cancer cells divert neuronal signaling molecules to redirect cellular trafficking machinery, thereby autonomously altering the TME and promoting resistance. Statement of Significance: Our study reveals an as-yet-undescribed molecular mechanism by which cancer cells can divert key neuronal molecules to regulate cellular trafficking and thereby autonomously modify the TME and promote resistance. It not only filled a crucial knowledge gap by elucidating how cancer cells autonomously modify cellular trafficking and the TME to resist therapy, but also suggest a novel therapeutic approach to address this challenge in contemporary targeted therapies. Declaration of interests: P.M. served as a scientific consultant to Accutar Biotechnology, Inc. T.W. is a scientific co-founder of NightStar Biotechnologies, Inc. H.L. is a shareholder and scientific advisor of Precision Scientific Ltd. All other authors declare that they have no competing interests. Citation Format: Ping Mu, Choushi Wang, Xiaoling Li, Su Deng. Prostate cancer exploits neurolysin to modulate the tumor microenvironment and therapy resistance via KIF11-mediated WNT secretion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6417.