Cellular metabolism and tumorigenesis: the role of growth hormone and mitochondrial dynamics in the Zebrafish experimental model

• Grant number: 20/06800-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): April 01, 2021
• Effective date (End): June 30, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Juliana Moreira Mendonça Gomes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology, AP.TEM

Abstract

Cancer is one of the major public health problems worldwide. Globally, except for non-melanoma skin carcinomas, breast Cancer is the most frequent malignant tumor among women and the fifth with the highest mortality rate. Anticancer therapies have improved treatments, but in many cases, these therapies do not fulfill their function, especially when the disease is at an advanced stage. Cancer research has been largely associated with genomic events such as gene mutations, oncogene amplifications and loss of tumor suppressor protein. However, recent studies have shown that cell metabolism acts as an important factor that contributes to tumor development and in the plasticity of the antitumor immune response. In fact, the metabolic reprogramming events in tumor cells meets the requirements of Cancer cell growth and maintenance. Some events such as energy metabolism and phenotypic changes in mitochondria have been considered a relevant target in the search for new therapies. The development and progression of the tumor in vivo has been evaluated through transplantation of human-derived tumor cells in different animal models. Zebrafish has emerged as a promise model among others by presenting unique features such as the use of few tumor cells in implants, optical clarity and rapid applicability in clinical tests. In addition, this model has histological, genetic and molecular similarities with humans. Several studies have demonstrated a positive relationship between the concentrations of GH (Growth Hormone) and IGF-1 (Insulin-like Growth Factor) with the risk of Cancer. Metabolic effects of the GH - IGF axis have been considered an important inducer of neoplastic tissue growth. IGF-1 expression is related to important signaling pathways involved in tumor progression, in this project we will highlight PI3K/Akt. Here, we formulate the hypothesis that events related to mitochondrial dynamics participate in the metabolic reprogramming that occurs in tumor cells and can influence GH-induced signaling pathways. To confirm our hypothesis, we will perform organoids xenotransplants of human breast tumor cells in wild and transgenic Zebrafish for GH. We will study tumor progression and protein and gene expression of molecules related to the PI3K/Akt signaling pathway, metabolic reprogramming (PDK1, ERK1/2 and p53) and mitochondrial dynamics (Mfn1/2 and Drp1). We will evaluate the morphological, metabolic and redox profile of the mitochondria present in xenotranced organoids. In in vitro assay, we will evaluate the mechanisms induced by GH that is involved in the unbalance of the mitochondrial dynamics of tumor cells through the silencing of the DRP1 gene. We believe that mitochondria have a central role in regulating the metabolism of Cancer cells and that cells depend on this metabolic reprogramming for their proliferation, ability to metastasize or resist apoptosis. The identification of a signaling network involved in the progression of Cancer has a potential application in clinical medical and can be used as a new target or synergistically associated with other drugs in the treatment of Cancer. (AU)