Investigating the role of retrotransposon and retrocopies activity in cancer and their implications for the origin and maintenance of tumor stem cells.

• Grant number: 23/11499-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2024
• End date: March 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Pedro Alexandre Favoretto Galante
• Grantee: Gabriel Arantes Galvão Dias dos Santos
• Host Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil

Abstract

Retrotransposons are a class of mobile DNA elements that utilize an RNA intermediate to move within the genome. These elements are categorized into LTR retrotransposons (derived from ancestral exogenous infections by retroviruses) and non-LTR retrotransposons (mainly LINEs and SINEs). Moreover, occasionally, the machinery of LINEs can capture other mature mRNAs (in trans) and re-insert them into the genome, forming retrocopies of coding genes, for example. mRNA retrocopies are gene duplicates characterized by retaining only the exons of the parent gene, lacking the regulatory regions (for transcription), and possessing the poly-A tail inserted into the genome. Although retroelements make up nearly 50% of the human genome, the majority of them are transcriptionally repressed in somatic cells. This changes under specific conditions, such as in cancer, where through epigenetic reprogramming, many of these elements are "reactivated" and expressed. Interestingly, in certain physiological processes, there is also reactivation of these elements, as seen in certain stages of embryogenesis. Research indicates that these retrotransposons play crucial roles in the phenotype of stem cells and in the acquisition of cellular pluripotency. Cancer stem cells (CSCs) are a specific type of cell within the tumor microenvironment responsible for cancer plasticity. These cells hold significant clinical importance as they correlate with highly aggressive, heterogeneous, and treatment-resistant tumors. Despite this, little is known about the complete gene expression profile of CSCs. Considering the role of retroelements in cellular pluripotency, we hypothesize that these elements have activity and functional roles in CSCs. Therefore, in this project, we aim to characterize the activity of retrotransposons and retrocopies, as well as the degree of stemness, in primary tumor samples, in order to identify potential implications of the activity of these mobile elements in the origin and maintenance of CSCs. This will be a comprehensive study involving over 10,000 samples from 12 tumor types, where we will not only investigate the detailed expression profile of retroelements and retrocopies but also the potential regulatory mechanisms of these elements in the origin and maintenance of stemness in tumors, as well as their impact on outcomes (e.g., overall survival) of cancer patients. We will also use single-cell RNA sequencing data from some tumors to directly investigate the expression of retroelements and retrocopies in CSCs and not in other cells of the tumor microenvironment. Finally, we will perform validations in cell lines to directly investigate the role of retroelements in cellular stemness. We believe that the results obtained here could contribute to a broader understanding of the relationship between retrotransposon activity and the origin of tumor stem cells, leading to advancements in the field of molecular oncology and catalyzing the development of innovative therapeutic strategies focused on retrotransposon activity for certain tumor types.