The Role of PTEN Gene Loss in Facilitating the Inflammatory Response in Prostate Cancer

• Grant number: 15/22785-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2016
• End date: March 31, 2019
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Jeremy Andrew Squire
• Grantee: Thiago Vidotto
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 17/08614-9 - The Role Of PTEN in STAT1 And STAT3 Mediated Inflammatory Response in Prostate Cancer, BE.EP.DR

Abstract

Prostate cancer (PCa) is the sixth most common type of cancer in the world and is also the most prevalent in men. Our preliminary data showed that there is increased expression of STAT1 and decreased STAT3 expression in PCa tumors with deletion of the PTEN gene. Since the STAT transcription factor family is involved in modulating immune response, this observation suggests that the inflammatory process that occurs in the tumor microenvironment in PCa may be influenced by PTEN gene loss. The rationale for this project is that the stroma of the PCa microenvironment is pro-tumorigenic by induction of pro-tumorigenic inflammatory cytokines. In this study, we will initially analyze public domain PCa expression data to investigate the modulation of RNA levels in genes where expression changes occur with loss of PTEN and they are also likely to be involved in pro-inflammatory signaling to the tumor microenvironment. We will then investigate the correlation between the deletion and expression status of the PTEN gene and the expression of genes associated with activation of inflammation in the microenvironment, together with an analysis of phosphorylation levels of STAT1 and STAT3, and the presence of immune cells in 150 PCa cases from HCFMRP-USP. We will use tumors from a retrospective cohort PCa from the HC and PCa cell lines of known PTEN deletion status. These experiments will establish a primary link between the deletion and expression of PTEN gene and the expression and activation of the signaling pathways triggering inflammation in the PCa tumor microenvironment and concomitant activation of STAT3 and STAT1. The evaluation of the presence or absence of PTEN gene associated with STAT1 and STAT3 together with the identification of novel immunological prognostic biomarkers will contribute to the development of innovative immunomodulatory therapies in PCa. Through bioinformatics analysis, we detected that STAT1 was upregulated in prostate cancer samples that had lost one or two copies of PTEN gene. We also found that immune and inflammatory response genes are overexpressed in tissues with PTEN loss, such as CXCL10, CXCL11, CXCL14, CD20, and CD276. We also detected, by immunohistochemistry, that STAT1 total protein was significantly increased in tumors with PTEN deletions. These results corroborate with the hypothesis that PTEN loss generates a pro-inflammatory tumor microenvironment that favors tumor progression. Detailed investigations will be performed to identify the specific role of PTEN gene loss in the immune and inflammatory response promotion.

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)

HARMON, STEPHANIE A.; PATEL, PALAK G.; SANFORD, THOMAS H.; CAVEN, ISABELLE; ISEMAN, RACHAEL; VIDOTTO, THIAGO; PICANCO, CLARISSA; SQUIRE, JEREMY A.; MASOUDI, SAMIRA; MEHRALIVAND, SHERIF; et al. High throughput assessment of biomarkers in tissue microarrays using artificial intelligence: PTEN loss as a proof-of-principle in multi-center prostate cancer cohorts. MODERN PATHOLOGY, v. 34, n. 2, SEP 2020. (15/09111-5, 17/08614-9, 15/22785-5)

VIDOTTO, THIAGO; MELO, CAMILA MORAIS; CASTELLI, ERICK; KOTI, MADHURI; DOS REIS, RODOLFO BORGES; SQUIRE, JEREMY A.. Emerging role of PTEN loss in evasion of the immune response to tumours. BRITISH JOURNAL OF CANCER, v. 122, n. 12, APR 2020. (15/09111-5, 17/08614-9, 15/22785-5)

VIDOTTO, THIAGO; TIEZZI, DANIEL GUIMARAES; SQUIRE, JEREMY A.. Distinct subtypes of genomic PTEN deletion size influence the landscape of aneuploidy and outcome in prostate cancer. MOLECULAR CYTOGENETICS, v. 11, JAN 3 2018. (15/09111-5, 15/22785-5, 16/02730-4)

Academic Publications

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

VIDOTTO, Thiago. Characterization of the genome and immune response in the tumor microenvironment of PTEN-deficient cancers. 2019. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.