Carvalho-Maia, C. | Search bioRxiv

bioRxiv2025

Intestinal stem cell marker MEX3A regulates PPARγ expression with functional impact in colorectal carcinogenesis

RNA-binding proteins (RBPs) are major effectors of post-transcriptional regulation. Recently, we described the role of MEX3A in maintaining intestinal stem cell identity and epithelial renewal by repressing the PPAR{gamma} pathway. This work aimed to study MEX3A functional impact in colorectal cancer (CRC). MEX3A and PPAR{gamma} expression profiles were characterized in murine and human models. CRISPR/Cas9-mediated MEX3A knockout was performed in patient-derived CRC tumoroids (PDCTs) and MEX3A RNA targets identified through the HyperTRIBE technique. Apc+/fl;Mex3a+/- mice presented a significant reduction in tumor burden. Apc+/fl;Kras+/G12D;Mex3a+/-mice presented a reduced tumor area, while corresponding tumoroids exhibited reduced growth and enhanced differentiation potential mediated by PPAR{gamma} signalling. MEX3A overexpression (85% of human CRC cases) was inversely correlated with PPAR{gamma} downregulation (72% of cases). Accordingly, MEX3A-depleted PDCTs showed decreased LGR5 expression, accompanied by increased PPAR{gamma} expression and higher sensitivity to 5-Fluorouracil/Oxaliplatin (FOLFOX)-based chemotherapy. The HyperTRIBE results revealed a direct interaction between MEX3A and PPARG transcripts. STATEMENT OF SIGNIFICANCEThese results emphasize that MEX3A plays a crucial role in colorectal carcinogenesis, partially through regulation of the PPARG pathway, mediating tumour development and response to therapy, thus constituting a potential therapeutic target.

cancer biology↗

bioRxiv2024

Deciphering the impact of cancer cells secretome and its derived-peptide VGF on breast cancer brain metastasis

Brain metastases (BM) are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we have searched for a brain-tropic metastatic signature on BC cells secretome, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Therefore, six specifically deregulated peptides were found to be enriched in the secretome of brain organotropic BC cells. Importantly, these secretomes caused significant blood-brain barrier (BBB) disruption, as well as microglial activation, in vitro and in vivo. We identified the VGF nerve growth factor inducible as a brain-specific peptide, promoting BBB dysfunction similar to the secretome of brain organotropic BC cells. Concerning microglial activation, a slight increase was also observed upon VGF treatment. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and in the adjacent stroma. VGF-positive tumors showed a significant worse prognosis and were associated with HER2 overexpression and triple-negative molecular signatures. Finally, in a cohort including primary breast tumors and their corresponding metastatic locations to the lung, bone, and brain, we found that VGF significantly correlates with the brain metastatic site. In conclusion, we found a specific BC brain metastatic signature, where VGF was identified as a key mediator in this process. Importantly, its expression was associated with poor prognosis for BC patients, probably due to its associated increased risk of developing BM.

cancer biology↗