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Modeling of the extracellular matrix and the epithelial-mesenchymal transition by histomolecular gradient in pulmonary neuroendocrine neoplasia for clinical decisions

Grant number: 23/09682-9
Support Opportunities:Scholarships in Brazil - Support Program for Fixating Young Doctors
Effective date (Start): August 01, 2023
Effective date (End): July 31, 2024
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Acordo de Cooperação: CNPq
Principal Investigator:Vera Luiza Capelozzi
Grantee:Tabatha Gutierrez Prieto Martins Rocha
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:23/01158-9 - Modeling of the extracellular matrix and the epithelial-mesenchymal transition by histomolecular gradient in pulmonary neuroendocrine neoplasia for clinical decisions, AP.R

Abstract

Background: Previous studies have described, through genomic analysis in tumor tissue, the investigation for the applicability of biomarkers associated with metastatic progression and death from cancer is mainly based on observations of the behavior of primary tumors. However, the studies do not prioritize the evaluation of biomarkers capable of identifying the effects of the stroma-associated fibrosis, in the tumor, that could be therapeutically relevant in metastatic lesions. Pulmonary neuroendocrine neoplasms (PNENs) are classified into four distinct groups: atypical (AC) and typical (TC) carcinoid tumors, large cell neuroendocrine carcinomas (LCNEC) and small cell lung carcinomas (SCLC). The behavior of these tumors is very diverse, while carcinoid tumors tend to be less aggressive, LCNEC and SCLC are often metastatic at the time of diagnosis and with a worse prognosis for the patient. The molecular mechanisms that lead to PNENs metastases remain largely unknown and require further studies. However, the identification of fibrotic genes in primary tumors and their effects on the tumor microenvironment (TME) as new biomarkers and therapeutic targets for PNENs appears to be promising. Since PNENs originate from neuroectodermal cells, factors responsible for activating the epithelial-to-mesenchymal transition (EMT) emerge as possible biomarkers involved in the genotypic transformation of these neuroectodermal cells, leading to changes in the final cell phenotype. In this scenario, additional markers, also applicable to biopsy specimens, that correlate the subtypes of PNENs with the response to systemic treatment, are essential, and the current potential candidates are the neurogenic EMT genes. Aim: In the present study, through a cohort of patients diagnosed with PNENs, we intend to evaluate expression profiles of fibrotic proteins, which are involved in the extracellular matrix (ECM) such as, (TGF-²1, COL1A2, COL3A1, COL5A2, ITGA5, ITGAV and ITGB1) and EMT-related proteins, including (BMP1, BMP7, CALD1, CDH1, EGFR, ERBB3, PLEK2, SNAI2, STEAP1, TCF4, CDH2, KRT14, CAV2, DSC2 and IL1RN) to elucidate how the involvement of these proteins may facilitate the mechanism of invasion and metastasis in PNENs. Materials and Methods: Tumor samples from a cohort of brazilian patients diagnosed with primary lung tumors - PNENs (atypical and typical carcinoids, n=100; large cell neuroendocrine carcinoma and small cell lung carcinoma, n=100), from the Instituto do Câncer do Estado de São Paulo (ICESP), the Hospital das Clínicas da Faculdade de Medicina da USP (HC-FMUSP) and the Instituto do Coração (Incor) will be submitted to the investigation of ECM fibrotic proteins and the expression of proteins related to EMT, evaluated through in situ assays. These assays consist of immunohistochemistry, immunofluorescence and semi-automated quantification. Furthermore, to evaluate the ECM matrisome, we will use Movat pentachrome staining. Thus, the expression of ECM and EMT proteins will be correlated with clinicopathological parameters and prognostic implications using the relevant statistical tests. Conclusion: Through the presented study, we infer that the possible differential patterns of ECM and EMT proteins founded in different histological subtypes of PNENs can improve the studies about the role of these proteins in the metastatic process and in the distinct behavior of these tumors. Furthermore, we intend to demonstrate that EMT and ECM proteins maintain a strong influence on the neuroendocrine cancer cells, permeating invasion and allowing metastasis with implications for patient survival.

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