Striking the evolutionary process of bone tumors

• Grant number: 21/06782-7
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Start date: February 01, 2022
• End date: January 31, 2027
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Mariana Camargo Maschietto
• Grantee: Mariana Camargo Maschietto
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
• Associated researchers: Ana Luiza Ongaro Seidinger Conte ; Maraysa de Oliveira Melo Stein ; Sam Behjati
• Associated research grant: 14/10250-7 - Characterization of the epigenetic regulation in human solid paediatric tumours, AP.JP
• Associated scholarship(s): 24/20428-0 - Characterization of the mechanisms involved with distinct methylation profiles between subgroups of osteosarcomas, BP.IC; 24/10105-9 - Characterization of the impact of mitochondria in the metabolism of osteosarcoma cells, BP.IC; 23/10527-8 - Characterization of telomere and associated genes in pediatric osteosarcomas, BP.IC; 22/04781-6 - Search for the molecular mechanisms involved with the tumorigenesis of bone tumors, BP.DD

Abstract

Molecular alterations increase the risk of cancer by increasing DNA damage, changes in the epigenome or the chromatin structure that impact the gene expression, metabolism and ultimately the phenotype exhibited by cancer cells. Identification of regulatory pathways and molecular biomarkers yielded dramatic changes in outcome for several adult cancers, but childhood cancer has largely been sidelined in this revolution. Even though bone tumors have high morbidity and mortality, there is limited knowledge regarding the underlying molecular mechanisms of their onset and progression. Most primary tumors of the bones are osteosarcomas and Ewing sarcomas. Probably related to their origins, their development and progression do not rely on mutation of single or few genes: while osteosarcomas present complex genotypes, Ewing sarcomas, an embryonic tumor, have highly variable epigenomes. We will explore bone tumors transformation, progression, relapse and treatment resistance using the epi/genomic instability as a driver of the cancer hallmarks. For that, the proposal is divided in five steps: (1) characterize the epi/genomic instability in osteosarcomas and Ewing sarcomas, (2) as well as the role of the telomeres, (3) explore the epigenome as a driver of the genomic instability, (4) search for a connection between the epi/genomic instability and an unbalanced metabolism, and (5) interfere with the mechanisms related to chemotherapeutic resistance. (AU)