Identification and analysis of long noncoding RNAs involved in the cancer stem cell phenotype in pancreatic cancer

• Grant number: 22/06092-3
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2022
• End date: September 30, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Daniela Sanchez Basseres
• Grantee: Daniela Sanchez Basseres
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Eduardo Moraes Rego Reis ; Ludmilla Thomé Domingos Chinen ; Roger Chammas

Abstract

Pancreatic ductal adenocarcinoma (PDAC), which represents over 90% of all pancreatic tumors, is a highly aggressive and lethal disease with a 5-year overall survival of less than 10%. This dismal prognosis is due, among other factors, to the early and extremely aggressive metastatic spread of this type of tumor coupled with resistance to chemotherapy. One of the most important hallmarks of metastatic capability and chemoresistance is the acquisition and maintenance of a stem-like phenotype by cancer stem cells (CSCs). CSCs comprise a subpopulation of tumor cells, that has an exceptional ability to initiate tumor formation and is thought to be responsible for tumor spread, growth of metastatic tumors and resistance to cytotoxic therapies. One major shortcoming that limits therapeutic advances in PDAC is that the mechanisms responsible for maintenanace of CSC subpopulations capable of metastatic spread and chemoresistance in PDAC are still poorly understood. Considering that acquisition of stem-like features is primarily an epigenetic process, we hypothesize that long noncoding RNAs (lncRNAs) are important players in establishing the stem-like phenotype in PDAC and, therefore, can represent promising progonostic biomarkers. This hypothesis is supported by different studies that show that lncRNAs regulate the epigenetic machinery and contribute to carcinogenesis, including several reports emphasizing the importance of lncRNAs in CSC biology in different tumor types. The goal of this project is to identify and functionally validate lncRNAs involved in promoting the CSC phenotype in PDAC. For this purpose, we will first analyze the global lncRNA transcriptional profile associated with the CSC phenotype using two different experimental models: 1) identify CSC-enriched lncRNAs in a model of patient-derived xenograft tumors representative of PDAC heterogeneity; and 2) identify lncRNAs correlated with the stemness index in PDAC patients using TCGA publicly available RNAseq datasets. Next, we will validate the differential expression of the identified lncRNAs in PDAC cell-based models enriched for CSCs, followed by identification of lncRNA-enriched pathways by gene co-expression network analysis. Finally, we will perform functional assays to evaluate the role played by lncRNAs in the pancreatic CSC phenotype in vitro and will determine the potential of identified lncRNAs to act as biomarkers in liquid biopsies of localized and metastatic PDAC patients. This acquired knowledge, not only will contribute to the identification of new biomarkers that can be used to predict prognosis and monitor tumor relapse, but also will provide important insights for the development of new adjuvant therapeutic approaches that will likely significantly improve PDAC patient prognosis. (AU)