Does ZEB1 cooperate with PTEN loss and TMPRSS2-ERG fusion in prostate cancer immune evasion?

• Grant number: 20/12816-9
• Support Opportunities: Scholarships in Brazil - Master
• Start date: April 01, 2021
• End date: September 30, 2022
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Jeremy Andrew Squire
• Grantee: Luiz Paulo Chaves de Souza
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Background: The first-line treatment for Prostate Cancer (PCa) patients is androgen deprivation therapy (ADT). Immunotherapy usually fails because PCa is an immunologically cold tumor. In 50% of PCa ETS gene is highly expressed because of fusion with the androgen-responsive TMPRSS2 gene. We have shown that PTEN loss may be involved in immune evasion in PCa. ETS overexpression induces disease progression and a pro-inflammatory gene signature in Pten deficient mice. ZEB1, a stem cell transcription factor that regulates epithelial-to-mesenchymal transition (EMT), is itself regulated by TMPRSS2-ERG fusion. Both PTEN loss and TMPRSS2-ERG fusion influence immune response in the tumor microenvironment (TME) of PCa. Also, acquisition of cancer stem-cell-like traits can change immune regulating activities in the TME. We propose that immune evasion response associated with PTEN loss and TMPRSS2-ERG in PCa is enhanced by ZEB1 transcriptional activity. Methods: We will characterize TME changes in PCa with PTEN +/-, TMPRSS2-ERG fusion +/- and ZEB1 +/- by in silico analysis and RNAseq expression targeting 395 immune response genes. Anticipated Results: We expect PTEN, TMPRSS2-ERG and ZEB1 to act together to enhance immune evasion by changes in gene expression that activate pathways that alter the immune cell content and trigger cytokine expression in the TME of PCa. Implications of study: Tumor genomics plays a crucial role in forming the immune response in the TME. Understanding the molecular relationships between PTEN loss, the presence of TMPRSS2-ERG fusion and ZEB1 expression will be helpful in future therapeutic inhibition studies to counter immune evasion in PCa. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CHAVES, LUIZ PAULO; MELO, CAMILA MORAIS; SAGGIORO, FABIANO PINTO; REIS, RODOLFO BORGES DOS; SQUIRE, JEREMY ANDREW. Epithelial-Mesenchymal Transition Signaling and Prostate Cancer Stem Cells: Emerging Biomarkers and Opportunities for Precision Therapeutics. GENES, v. 12, n. 12, DEC 2021. (19/22912-8, 20/12816-9)

MELO, CAMILA MORAIS; VIDOTTO, THIAGO; CHAVES, LUIZ PAULO; LAUTERT-DUTRA, WILLIAM; REIS, RODOLFO BORGES DOS; SQUIRE, JEREMY ANDREW. The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 17, SEP 2021. (19/22912-8, 20/12816-9)

VIDOTTO, T.; MELO, C. M.; LAUTERT-DUTRA, W.; CHAVES, L. P.; REIS, R. B.; SQUIRE, J. A.. Pan-cancer genomic analysis shows hemizygous PTEN loss tumors are associated with immune evasion and poor outcome. SCIENTIFIC REPORTS, v. 13, n. 1, p. 13-pg., 2023-03-28. (20/12816-9, 19/22912-8, 21/12271-5)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SOUZA, Luiz Paulo Chaves de. Expression of epithelial-mesenchymal transition markers SNAI1 and ZEB1 results in transcriptional alterations that promote tumor progression and immune evasion in prostate cancer. 2023. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.