The role of the mTOR pathway in cancer cachexia: a post-mortem neuropathological study

• Grant number: 18/24557-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: February 02, 2019
• End date: February 01, 2020
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Marilia Cerqueira Leite Seelaender
• Grantee: Estefania Simoes Fernandez
• Supervisor: Gabriele Carmine de Luca
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Oxford, England
• Associated to the scholarship: 16/12508-7 - Hypothalamic changes related to the syndrome of cachexia associated with cancer: morphological analysis and histological, molecular, cellular and systemic central nervous system study, BP.DD

Abstract

Cancer cachexia is a multifactorial and systemic syndrome whose aetiology remains elusive. Clinically, cancer cachexia has been defined as a "muscle-wasting syndrome that compromises therapeutic approaches, leads to a poor prognosis, reduced survival and is directly correlated with death in up to 40% of cancer patients". Available evidence suggests that systemic inflammation which characterise the syndrome leads to CNS dysregulation and neuroinflammation that impact on neural circuits controlling feeding behaviours and body composition. Given the central role of the mechanistic target of rapamycin (mTOR) pathway in regulating anabolic processes integral for weight homeostasis, such as protein and lipid synthesis, there is an increasing interest in the possible contribution of mTOR in cancer cachexia. Recent work in our group has identified brain regions (hypothalamus, amygdala, and basal ganglia) that show significant structural differences in cachectic cancer patients. However, the underlying neuropathological substrate and the role of the mTOR pathway in mitigating these structural changes is still unknown and become the focus of this study. In order to elucidate the human cachectic brain, the aim of this internship is to analyse a human autopsy cohort of patients who died of carcinoma with cachexia (n=10) and without cachexia (n=10), and age- and sex-matched non-neurologic controls (n=10) derived from the Oxford Brain Bank. On the one hand, we will evaluate the extent of neuronal and synaptic loss (NeuN and MAP2) and CNS immune cells profile [microglial/macrophage, (Iba1+ for total microglia and PG-M1 for activated microglia), T-cell infiltration (CD3+), and complement (C9neo) deposition]. On the other hand, to provide a global measure of mTOR activity, the distribution and extent of a subset of core upstream (TSC1 and TSC2) and downstream (mTOR and S6K, phos and non-phos variants) mTOR-related pathway proteins will be assessed. (AU)