Microbiota regulation of prostate cancer growth and metastatic dissemination

Microbiota are microorganisms living in symbiosis with the host, being fundamental to homeostasis. Imbalances in these bacterial communities, termed dysbiosis, have been described and are associated with multiple pathologies, including cancer. This proposal is structured with four different Aims, which are tightly interconnected but independent from each other. Aim 1 will assess whether and how the gut or intratumoral microbiota promote metastases formation in prostate cancer (PCa). Preliminary data collected by my team through immunohistochemistry and 10x single-cell analyses demonstrate the presence of intratumoral bacteria in metastatic tumor lesions of patients affected by PCa. We therefore hypothesize that: 1) intratumoral bacteria hijack circulating tumor cells (CTC) to enhance their metastatic capability and/or 2) commensal bacteria are recruited in CTC clusters or in metastatic tumor lesions to support metastatic seeding and growth. In Aim 2, we will develop a drug discovery platform to identify microbiome-derived therapeutics to treat primary and metastatic prostate cancer. We have found that the supernatant of Prevotella Stercorea, a gut commensal bacteria found enriched in the stools of patients associated with a favorable prognosis, can suppress prostate cancer growth without halting normal cell proliferation. Therefore, we aim to assess whether additional bacteria associated with a favorable prognosis in castration resistante prostate cancer (CRPC) patients produce metabolites and/or small molecules that suppress prostate tumor cell proliferation and metastases. Aim 3 will focus on the generation of Live Biotherapeutic Products (LBPs) for the treatment of prostate cancers. We will engineer LBPs with bacterial small molecules identified in Aim 1 to assess whether they can antagonize the development of metastatic PCa. These bacteria will also be used in combination therapies to assess if they can improve the efficacy of the standard of treatments in PCa. Finally, in Aim 4 we will assess the efficacy of available therapies targeting the gut microbiota in CRPC patients and develop a novel fecal biomarker for the detection of the unfavorable microbiota. We have previously demonstrated that antibiotic treatments in different GEMMs and PDX models block CRPC development. I now plan to assess in a clinical trial whether this combined treatment can also affect CRPC development and impact metastasis formation in PCa patients. In this respect, my team has already proved in the past the capability to translate novel pre-clinical findings to the clinic.