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

Author:

Sulsenti Roberta1ORCID,Scialpi Giuseppina B.1ORCID,Frossi Barbara2ORCID,Botti Laura1ORCID,Ferri Renata1ORCID,Tripodi Irene1ORCID,Piva Annamaria1ORCID,Sangaletti Sabina1ORCID,Pernici Davide1ORCID,Cancila Valeria3ORCID,Romeo Francesco4ORCID,Chiodoni Claudia1ORCID,Lecis Daniele1ORCID,Bianchi Francesca5ORCID,Fischetti Irene1ORCID,Enriquez Claudia1ORCID,Crivelli Filippo6ORCID,Bregni Marco6ORCID,Renne Giuseppe7ORCID,Pece Salvatore4ORCID,Tripodo Claudio3ORCID,Pucillo Carlo E.2ORCID,Colombo Mario P.1ORCID,Jachetti Elena1ORCID

Affiliation:

1. Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. 1

2. Immunology Section, Department of Medicine, University of Udine, Udine, Italy. 2

3. Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy. 3

4. Dipartimento di Onologia Sperimentale, European Institute of Oncology IRCCS, Milan, Italy. 4

5. Microenvironment and Biomarkers in Solid tumors Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. 5

6. Oncology-Hematology Unit, ASST Valle Olona, Busto Arsizio, Italy. 6

7. Uropathology and Intraoperative Diagnostic Division, European Institute of Oncology IRCCS, Milan, Italy. 7

Abstract

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

Funder

Ministero della Salute

Fondazione AIRC per la ricerca sul cancro ETS

Publisher

American Association for Cancer Research (AACR)

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