Abstract 3161: The perlecan-semaphorin3A-plexinA1-neuropilin-1 Complex: Toggle control of prostate cancer cycles of dormancy and reactivation
Authors: Tellman Tristen V. , Sablatura Lindsey K. , Cruz Lissette A. , Lin Sue-Hwa , Chung Leland W. , Farach-Carson Mary C. 
Published: July 2021

Introduction: Metastatic prostate cancer (PCa) undergoes cycles of dormancy and reactivation, resulting in secondary metastasis, and leading to lethal disease. PCa preferentially metastasizes to bone where it can remain dormant for years after initial colonization. Previous work showed different growth and dormancy phenotypes in PCa tumors injected subcutaneously and intrafemorally, though the exact source of the dormancy-inducing factors remains undefined. We identified a novel receptor complex, the Perlecan-Semaphorin3A-PlexinA1-Neuropilin-1 (PSPN) complex, that is modulated by context-specific endothelial cell populations. The overall goal of this project is to identify the role of endothelial cells in stabilizing and silencing metastatic behavior via the PSPN complex, it's downstream pathways, and it's turnover by matrix metalloproteinase 7/Matrilysin (MMP-7).

Methods: Live/dead assays coupled with immunolabeling and molecular approaches were used to determine the molecular impact of secreted endothelial cell factors on PCa signaling and behavior through the PSPN Complex in 2.5D and 3D microtumor cultures. Reverse phase protein arrays (RPPA) provided an unbiased means to assess the downstream molecular events in 3D co-cultures of PCa and microvascular cells.

Results: Intact perlecan (P) induced clustering via engagement of PSPN complex. Destruction of complex components by MMP-7 activated growth and migration. FOXM1 was activated downstream of PSPN complex cleavage and resulting destabilization, consistent with escape from dormancy. Secreted factors from endothelial cells induced dormancy and reduced FOXM1 activation. Immunolocalization data showed internalization of plexin A1 with immunostaining both at the PCa cell surface and perinuclear, consistent with dynamic turnover associated with activation of signaling after loss of the PSPN complex.

Conclusion: Intact PSPN complex at the PCa cell surface favors a dormant state that is reversed by MMP7 cleavage. In the cohesive state (PSPN complex intact) FOXM1 is “off”, inhibiting the transcription of growth and metastasis promoting factors. Context-specific endothelial cell populations secrete PSPN complex stabilizing proteins, silence downstream signaling, and result in a dormant phenotype. We propose that the PSPN complex at metastatic sites such as bone acts as a molecular toggle that can maintain dormancy until the switch is “flipped” by MMP-7 allowing reactivation, dyscohesion and favoring growth and metastasis.

Citation Format: Tristen V. Tellman, Lindsey K. Sablatura, Lissette A. Cruz, Sue-Hwa Lin, Leland W. Chung, Mary C. Farach-Carson. The perlecan-semaphorin3A-plexinA1-neuropilin-1 Complex: Toggle control of prostate cancer cycles of dormancy and reactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3161.