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Effect of the aged-related changes in tumor microenvironment in the angiogenesis and lymphangiogenesis

Grant number: 17/07010-2
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): August 01, 2017
Effective date (End): January 31, 2018
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Silvya Stuchi Maria-Engler
Grantee:Débora Kristina Alves Fernandes
Supervisor: Ashani T. Weeraratna
Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Wistar Institute, United States  
Associated to the scholarship:14/06959-0 - Evaluation of the potential for overcoming melanoma chemoresistance to BRAF V600E (Vemurafenib) and MEK (Trametinib) inhibitors using combined therapy with 4-nerolidylcatechol (4-NC), BP.DR


Melanoma represents the deadliest of all skin cancers. The comparison of melanoma incidence and mortality rates indicated a worse prognosis with increasing age. Patients with melanoma demonstrated an inverse correlation of melanoma mortality and incidence of sentinel node metastasis in young and old patients. The Wnt5A and HAPLN1 proteins are altered in the aged microenvironment, they seem to be contributors to alterations in extracellular matrix (ECM) integrity, and can influence broadly to the metastatic progression, resistance therapy, and poor prognosis. This project aims to investigate the age-related ECM alterations. Specifically, in vitro studies will be focused on the role of Wnt5A and HAPLN1 proteins in young and aged fibroblasts evaluated by production of cross-linking alterations of collagen protein and ECM integrity. Whether the activation of angiogenesis process compromises the lymphatics vessels and if it results in a hematogeneous route of dissemination will be also a main question of this work. For this, we will build 3D reconstructed skin models using dermal endothelial cells, young and aged fibroblasts with manipulated genes and melanoma cells and we will determine the ECM integrity by specific markers (CK10, CK14, and DDR1) and by microscopy images (Second Harmonic Generation Microscopy). Quantification of invasion of melanoma cells will be performed using ImageJ software. Furthermore, we will also assess the angiogenic (VEGF, bFGF) and lymphangiogenic markers (VEGFC, VEGFD and EGF) by ELISA and by IHC (CD31 and thrombospondin-1, respectively). Using this aged capillarized reconstructed skin, we expect to demonstrate the role of aged microenvironment modulating/impairing the formation of capillary-like tubes, thus modifying the angiogenesis and lymphangiogenesis process.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ALVES-FERNANDES, DEBORA KRISTINA; DE OLIVEIR, ERICA APARECIDA; FAIAO-FLORES, FERNANDA; ALICEA-REBECCA, GRETCHEN; WEERARATNA, ASHANI T.; SMALLEY, KEIRAN S. M.; DE MORAES BARROS, SILVIA BERLANGA; MARIA-ENGLER, SILVYA STUCHI. ER stress promotes antitumor effects in BRAFi/MEKi resistant human melanoma induced by natural compound 4-nerolidylcathecol (4-NC). PHARMACOLOGICAL RESEARCH, v. 141, p. 63-72, . (17/07010-2, 17/04926-6, 14/06959-0, 14/24400-0)
ALVES-FERNANDES, DEBORA KRISTINA; DE OLIVEIRA, ERICA APARECIDA; HASTREITER, ARACELI APARECIDA; FAIAO-FLORES, FERNANDA; FELIPE-SILVA, ALOISIO SOUZA; TURATO, WALTER; FOCK, RICARDO AMBROSIO; MARIA-ENGLER, SILVYA STUCHI; DE MORAES BARROS, SILVIA BERLANGA. In vivo antitumoral effect of 4-nerolidylcatechol (4-NC) in NRAS-mutant human melanoma. Food and Chemical Toxicology, v. 141, . (17/07010-2, 14/24400-0, 14/06959-0, 17/04926-6)

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