Data from Intracellular Osteopontin Promotes the Release of TNFα by Mast Cells to Restrain Neuroendocrine Prostate Cancer

• DOI: 10.1158/2326-6066.c.7429384.v1
• Publication Date: 2024-09-03T07:31:20Z
• Authors: Roberta Sulsenti; Giuseppina B. Sci...; Barbara Frossi; Laura Botti; Renata Ferri; Irene Tripodi; Annamaria Piva; Sabina Sangaletti; Davide Pernici; Valeria Cancila; Francesco Romeo; Claudia Chiodoni; Daniele Lecis; Francesca Bianchi; Irene Fischetti; Claudia Enriquez; Filippo Crivelli; Marco Bregni; Giuseppe Renne; Salvatore Pece; Claudio Tripodo; Carlo E. Pucillo; Mario P. Colombo; Elena Jachetti
• Keywords: Osteopontin; Mast (botany)

<div>Abstract<p>Neuroendocrine prostate cancer (NEPC) is an aggressive form of that emerges as tumors become resistant to hormone therapies or, rarely, arises <i>de novo</i> in treatment-naïve patients. The urgent need for effective against NEPC hampered by the limited knowledge biology governing this lethal disease. Based on our prior observations transgenic adenocarcinoma mouse (TRAMP) spontaneous model, which genetic depletion either mast cells (MC) or matricellular protein osteopontin (OPN) increases frequency, we tested hypothesis MCs can restrain through OPN production, using <i>in vitro</i> co-cultures between murine human tumor cell lines and MCs, vivo</i> experiments. We unveiled a role intracellular isoform OPN, so far neglected compared with secreted isoform. Mechanistically, unraveled promotes TNFα production via TLR2/TLR4-MyD88 axis, specifically triggered encounter cells. found MC-derived TNFα, turn, growth NEPC. then identified syndecan-1 (SDC1) NEPC-specific TLR2/TLR4 ligand pathway. Interrogating published single-cell RNA-sequencing data, validated mechanism different model. Translational relevance results was provided silico</i> analyses available datasets immunofluorescence patient-derived lesions. Overall, show actively inhibit NEPC, paving way innovative MC-based fatal tumor. also highlight SDC1 potential biomarker incipient NEPC.</p></div>