Establish patient-derived organoid models for pre-clinical study and interaction of Prostate Cancer (PCa) with the tumor microenvironment (TME)

• Grant number: 24/05784-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Jeremy Andrew Squire
• Grantee: Nilton José dos Santos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 21/15011-4 - Single-cell transcriptomics and in vitro characterization of the molecular causes of immunotherapy failure in advanced prostate cancer, AP.TEM

Abstract

Prostate cancer (PCa) is the most commonly diagnosed malignant tumor in men and the second leading cause of cancer-related mortality. Despite the high long-term survival in localized prostate cancer, metastatic disease remains largely incurable even after intensive multimodal therapy. Even with immunotherapy, which has improved patient survival in many types of cancers, PCa results have been disappointing. The lethality of advanced PCa is driven by the lack of therapeutic regimens capable of generating durable responses in the setting of extreme tumor heterogeneity at the genetic and cell biological levels. Our hypothesis is that PTEN loss induces transcriptional and downstream changes in metastatic PCa that activate both the classical tumor-promoting PI3K-mTOR pathway, and a tumor microenvironment associated with immune evasion. Thus, PTEN loss would be a major reason for immunotherapy failure in metastatic PCa.Our limited understanding of what drives the aggressive behavior of advanced PCa and what molecular pathways underlie their failure to respond to various drug therapies underscores the need to study tumors in vitro so that more effective therapies can be evaluated. Tumor organoids have become such a strong model because they allow patient-derived cancer cells to form 3D structures in culture that faithfully mimic the tumor architecture. They maintain cell-cell and cell-matrix interactions, intra- and inter tumor-heterogeneity that facilitates appropriate oxygen, nutrient and drug concentration gradients that closely mirror in vivo conditions. This new in vitro approach allows for tumor microenvironment reconstruction, thus emerging as one of the most physiologically relevant ways for functional assays.The aim of this project is to establish the organoid model systems of advanced PCas, which will enable us to address the biology of the prostatic cancer cells regarding i) molecular mechanisms of drug resistance and ii) interaction with the tumor microenvironment at individual level, thus paving the path towards personalized medicine.