Aging and response to chemotherapy during the treatment with collagen peptides: Reconstruction of aged human skin in vitro to study the invasion of melanoma resistant to treatment with B-RAF inhibitor

• Grant number: 20/14919-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2022
• End date: April 01, 2026
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Silvya Stuchi Maria-Engler
• Grantee: Renaira Oliveira da Silva
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/04926-6 - Melanoma and chemoresistance: in vitro and in silico models to exploit therapeutic targets, AP.TEM
• Associated scholarship(s): 23/08844-5 - Targeting YAP/TAZ-tead activity in drug-tolerant aged melanoma, BE.EP.DR

Abstract

Aging is the most significant demographic risk factor for cancer development, indicating that molecular changes during the process are a trigger for malignant transformation. Melanoma is a cancer with a high probability of metastasis and a high rate of resistance to conventional therapies, resulting in a worse prognosis especially for the elderly. Physiological processes such as the accumulation of advanced glycation end products (AGEs) or external ones, such as ultraviolet (UV) radiation, contribute to cell / tissue aging associated with phenomena such as atrophy, loss of healing capacity and skin elasticity, representing changes in extracellular matrix (ECM) that facilitate the metastatic progression of melanoma skin cancer. Changes in connective tissue involving the differential crosslink of MEC components, such as collagen, place fibroblasts as central players in the invading niche. In this context, assessing how the microenvironment, which is deeply altered by aging, contributes to the ability to invade cutaneous melanoma and, in particular, chemoresistant melanoma, is fundamental for the adoption of new therapeutic strategies. Ingestion of hydrolyzed collagen changed the dermis of patients, improving firmness and elasticity in a double blind clinical study. The use of hydrolyzed collagen peptides has been shown to reduce the activity of an enzyme active in ECM and to increase the expression of collagens I and IV on the metabolism of rat skin. On the other hand, the effects in a patient with melanoma are not explored. This project aims to reconstruct human skin aged in vitro by dermal glycation, to include metastatic melanoma to evaluate the effect of adding hydrolyzed collagen peptides at the following points: 1) Changes in the collagenous web in the invasive niche of cells resistant to the inhibitor of B-RAF; 2) Characterization of the secretome of the three-dimensional glycated skin system containing resistant melanoma. Once the secretoma is characterized, 3) we will explore pro-tumor cytokines (IL-6 and IL-8) and enzymes active in the remodeling of the extracellular matrix (MEC), such as MMPs. Thus, we intend to contribute to the understanding of the action of collagen peptides in the conformation of MEC through the glycation phenomenon, characterizing the factors common to aging in the progression of melanoma with emphasis on the resistance process. These results will provide the molecular basis for clinical understanding of the process of metastasis and failure of therapy in patients with advanced age, and may bring new possibilities for treatment and control of the disease.