Dados do Resumo

Título

INVESTIGATION OF SIGNALLING PATHWAYS AND GENES NETWORKS PLAYED BY CD90/THY1 IN TRIPLE NEGATIVE BREAST CANCER

Introdução

Breast cancer is the most prevalent type of tumour in the world, and the second in Brazil, with triple-negative (TNBC) being the most aggressive subtype of them all, with no specific therapeutic target to date. In the meantime, our group studying the CD90 biomarker demonstrated promising results, possibly representing a promising diagnostic and therapeutic target. However, the complex interactions between CD90 and its association with other signalling pathways remain elusive.

Objetivo

To address this knowledge gap, we employed a whole-transcriptomics and proteomics approach using a CD90-edited TNBC-derived cell line model, MFC10A wild type and overexpressing CD90, as well as Hs578T wild type and silenced for CD90 via viral vector.

Métodos

Differentially Expressed Genes (DEGs) were identified using the DESeq2 and edgeR methods, applying specific criteria for Fold Change (FC) and False Discovery Rate (FDR). DEG-based enrichment analysis was conducted for each treatment of MCF10A/CD90+ (A) and Hs578T/shCD90 (B) cell lines using the EnrichR tool with the KEGG+Reactome database. A new RNA-seq analysis strategy was proposed based on cellular model assays and gene sets selected from molecular signature databases (MsigDB). Each analysis was performed using the fGSEA software, considering the expression profiles in the Gene Set Enrichment Analysis (GSEA) and groups identified by PCA. Weighted gene co-expression network analysis (WGCNA) was further conducted to integrate pathways enriched with PCA results. Furthermore, based on current literature, a list of genes and canonical pathways related to TNBC was assembled and used as a model validation step, and its results after enrichment and biological correlations.

Resultados

Based on existing literature, we identified 151 canonical genes and 65 pathways associated with TNBC. 14 canonical genes were identified from the DEGs in set A, while only 3 were found for set B. PCA analysis revealed two distinct groups of pathway sets segregating cells A and B, highlighting five critical pathways involved in contrasting biological processes to the overexpression of CD90 and its inhibition in the cellular models studied, as well as in in vivo assays, there was proof of concept of the phenotypic change of CD90+ or ​​CD90- cells.

Conclusões

Thus, RNA-seq results aim to identify overexpressed and co-expressed genes, offering insights into the specific mechanisms that drive the phenotypes of our edited cell model, aiming to better understand the pathways and genes related to the functioning of CD90 in the process of normal and pathological cellular, as there is no understanding of how it manages to modulate carcinogenesis and it is related to the worst types of tumours, as already evidenced by the literature for different tumour types.

Financiador do resumo

CAPES, CNPq, FAPESP

Palavras Chave

TNBC; breast cancer cell model; biomarker