Functional analysis of HOXD10 in pediatric osteosarcoma with emphasis on invasion and metastasis

• Grant number: 16/19226-7
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2017
• End date: April 30, 2021
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: María Sol Brassesco Annichini
• Grantee: María Sol Brassesco Annichini
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Edgard Eduard Engel ; Nelson Fabrício Gava

Abstract

Osteosarcoma is the most common pediatric bone tumor primarily found in long bone metaphyses. Current treatment consists of surgical removal and neoadjuvant multimodal chemotherapy. About one third of patients are affected by post-surgery recurrence and distant metastases in the lungs and bones. Only 20% of patients with metastases survive after 5 years. Therefore, it is essential to elucidate the molecular pathways involved in the invasive and metastatic process of this tumor. Recently several studies have indicated the HOXD10 transcription factor as a general inhibitor of cell invasion. In general, the members of the HOX family genes are considered important cellular regulators, mainly involved in embryonic development, pluripotency maintainance and promote cell differentiation in multicellular organisms in a controlled manner. Deregulation of several HOX genes has been associated with tumor development and progression. Evidence suggests that most upregulated HOX genes found on a particular cancer in a body region is usually expressed during the development of such local. Interestingly, HOXD and HOXA gene clusters are responsible for the development of normal bone tissue and altered HOXD10 expression specifically, results in defects in the hind limbs of mice. Thus, although mainly described as hyperexpressed in cancer, preliminary studies performed by our group have shown that this gene is scarcely expressed in mature bone tissue while hiighly expressed in pre-chemotherapy osteosarcoma samples. Similar results have been reported in head and neck carcinoma and Ewing's sarcoma. In these studies, HOXD10 promoted migration and proliferation but little is known of the molecular mechanisms underneath such effects. Thus, this project aims to study the HOXD10 expression profile in primary and mestastatic osteosarcoma samples and to evaluate the in vitro and in vivo effects of its modulation (silencing through CRISPR and amplification with lentiviral vector) on the invasive and proliferative capacity of this tumor. Moreover, we aim to elucidate the mechanisms underneath HOXD10 modulation through large scale gene expression profiling and validation. (AU)