MOLECULAR, TRANSCRIPTOMIC, PROTEOMIC AND METABOLOMIC ASPECTS OF CAQUEXIA IN A PRE-CLINICAL AND CLINICAL MODEL

• Grant number: 23/00608-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: July 01, 2025
• End date: June 30, 2030
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Maria Cristina Cintra Gomes Marcondes
• Grantee: Maria Cristina Cintra Gomes Marcondes
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Adam Watkins ; Alexander Birbrair ; André Gustavo de Oliveira ; Andre Schwambach Vieira ; Gabriela de Matuoka e Chiocchetti ; Guilherme Augusto da Silva Nogueira ; José Barreto Campello Carvalheira ; Laís Rosa Viana ; Leisa Lopes Aguiar ; Maria Carolina Santos Mendes ; Natália Miyaguti Angelo da Silva ; Sílvio Roberto Consonni ; Steven Thomas Russell

Abstract

The main objective of our laboratory is to elucidate the metabolic and molecular effects of the development of cancer-induced cachexia. Cachexia, imposed by cancer, is considered one of the main problems in treating solid tumours, particularly of the pancreas, stomach, lung and colon; there is an intense wasting of host tissues, especially skeletal muscle. On the other hand, in these patients, the cachexia seems to be mediated instead by catabolic factors, intense alteration of genic expression, and activation of signalling pathways imposed by tumour development. During pregnancy, neoplastic disease is significant, more than its incidence, but by its coexistence with another complex metabolic condition, including two patients: mother and foetus. Thus, knowledge of the transcriptomic, proteomic and metabolomic profiles and the molecular mechanism of cachexia could be used to improve the clinical treatment of these patients. Therefore, our research work (until then funded by FAPESP) aims to investigate the effects of the growth of experimental tumours, models of cachexia (such as Walker's tumour, MAC16 and C26 colon adenocarcinoma, and Lewis carcinoma, experimental models of cachexia), on carcass spoliation and especially the mechanisms involved in protein catabolism and inhibition of muscle protein synthesis of these animals. Currently, our main interest is to elucidate the mechanism of tissue protein turnover in vivo and in vitro assays, besides relating the possible metabolic pathways involved in the modulation of carbohydrate and protein metabolism in muscle, liver, heart, and adipose tissues, since cachexia is considered a systemic paraneoplastic phenomenon in which crosstalk communication can be a critical component in its pathophysiology. Considering this, we intend to systematically study the influence and interaction of different tissues - adipose, cardiac, and hepatic on the process of loss of muscle mass by translating the experimental animal model assays to the clinic. This translational approach will undoubtedly enable a better understanding of cancer cachexia and will allow us to design future strategies as specific interventions to prevent or reverse cachexia. Thus, realising the translation to the clinic as an innovative point for this project, analysis of the clinic will be compared to preclinical experiments, bringing advances in the evaluation of biochemical and molecular processes of cell signalling and also involved with metabolomic and proteomic profiles, and especially with transcriptomics and association with microRNAs, since it is necessary to know more about the role of interaction between molecular components and the degree of enrichment of pathways and biological processes observed in the data obtained from omics analyses in the cachexia process in pre-clinic and clinic data. Thus, identifying specific genes related to cachexia in a time-course study and the modulation by nutritional supplementation may allow possible strategies to treat cachexia. These analyses can allow the best characterisation of signalling pathways and their interactions in both translational preclinical models and clinics and as a special interest in the investigation of cellular signalling processes involved in the activation of catabolism and protein synthesis in the disarrangement of the host tissue as a function of tumour growth when associated with nutritional leucine supplementation. Thus, in this thematic project, we propose to group the different projects developed in our laboratory (described as subprojects), such as nutrition and cancer associated with pregnancy, development, ageing and physical activity, aiming that the basic knowledge can provide translation to the clinic since we will evaluate patients with cachectic colorectal cancer compared to non-cachectic cancers. We intend to systematically study the influence of adipose, hepatic and cardiac tissues on the process of loss of muscle mass. Finally, we will eval (AU)