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

Sulsenti, Roberta (2023). Intracellular Osteopontin Controls the Release of TNFα by Mast Cells to Restrain Neuroendocrine Prostate Cancer. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00015856

Abstract

Fatal neuroendocrine prostate cancer (NEPC) often emerges in patients relapsing after hormone therapies. Besides, de-novo NEPC can rarely occur in treatment- naïve patients. The poor knowledge of mechanisms fostering NEPC growth hampers the development of effective therapies.

Investigating the tumour microenvironment, we found that mast cells (MCs) accumulate within hormone-sensitive prostate cancer favouring its growth, whereas are excluded by de-novo NEPC both in patients and in the TRAMP transgenic mouse model. Also, TRAMP mice backcrossed with MCs-deficient Kit^Wsh mice showed increased frequency of de-novo NEPC. NEPC incidence similarly raised in TRAMP mice deficient for the matricellular protein osteopontin (OPN). Reconstituting Kit^Wsh-TRAMP mice with wild type (WT), but not with OPN^-/- MCs, lowered the frequency of NEPC to that of untreated TRAMP mice, suggesting that MCs exert their NEPC protecting function through OPN.

We found that both tumour-infiltrating and in-vitro cultured MCs stain positive for OPN but release a tiny amount of OPN in supernatants if compared to NEPC cells. Notably, OPN has both secreted (sOPN) and intracellular (iOPN) forms; the latter can bind to MyD88 and regulate the signalling downstream toll-like receptors (TLRs). We then hypothesized that iOPN in MCs can control the TLR-dependent release of antiproliferative cytokines.

Indeed, WT, but not OPN^-/- or MyD88^-/-, MCs inhibited the proliferation of NEPC cells in vitro. This effect was mediated by tumor necrosis factor alpha (TNFα), specifically secreted by MCs after the contact with NEPC cells. We confirmed that MCs infiltrating both murine and human incipient NEPC lesions express TNFα. Moreover, the reconstitution with TNFα^-/- MCs did not reduce the abnormal frequency of NEPC in Kit^Wsh-TRAMP mice. In human and murine data sets of overt NEPC, genes related to TLRs signalling, including TNFα were downregulated.

Our data indicate that TLRs/MyD88/iOPN-mediated pathways induce MCs to release TNFα to restrain NEPC, suggesting investigating MC-based approaches for NEPC.

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