How changes in gene expression in immune and stromal cells are affect by PTEN loss?

• Grant number: 25/00553-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2025
• End date: March 31, 2027
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Jeremy Andrew Squire
• Grantee: Fabiana de Oliveira Buono
• 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 overall hypothesis is that metastatic PCa that fail to respond to immunotherapy often have PTEN loss together with other mutational changes that lead to transcriptional alterations in the tumor that influence the immune cells and secreted cytokines in the TME, facilitating immune evasion. In our experimental design, the scRNA-seq will be applied to increase the depth of TME analyses available by flow cytometry and immunofluorescence spatial imaging (provided by PD-1). The method is ideal for detecting very rare subpopulations (less than 0.1%), such as cancer stem cells, drug-resistant cells, migratory cells that underlie metastasis and immune infiltrating lymphocytes that escapes detection by most methods. Our study will highlight the potential of scRNA-seq to increase our understanding of the cell types in the tumor microenvironment that mediate immune evasion when PTEN is lost in metastatic PCa. We will distinguish and classify the different immune cell subsets based on their expression profiles derived from scRNA-seq.