Biology subjects

Vidal-Sabanes, M.

Publications and source records attributed to Vidal-Sabanes, M..

4 recordsLinked to original sources

bioRxiv2025

miR-424(322)~503 impairs colon cancer progression driven by PTEN deficiency.

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide, with molecular subtypes and signaling pathways playing critical roles in its progression. The miR-424(322)[~]503 cluster, comprising miR-424 and miR-503, has been implicated in various malignancies, exhibiting dual roles as tumor suppressors or oncogenes depending on the context. However, its function in CRC remains poorly understood. This study investigates the role of the miR-424(322)[~]503 cluster in CRC driven by PTEN deficiency using genetically modified mouse models. Our findings reveal that the loss of miR-424(322)[~]503 significantly exacerbates CRC progression in PTEN-deficient mice. Double knockout (dKO) mice lacking both PTEN and miR-424(322)[~]503 exhibited a higher number and larger size of colorectal lesions compared to PTEN-deficient counterparts. Histological analysis demonstrated increased severity of dysplasia and adenocarcinoma development in dKO mice. Mechanistically, while Wnt/{beta}-catenin signaling remained unaltered, transcriptomic analyses highlighted dysregulation of MAPK and TGF{beta} pathways, alongside epithelial-to-mesenchymal transition (EMT)-related gene signatures. Protein-level validation confirmed hyperactivation of MAPK (ERK1/2 and p38) and TGF{beta} signaling, as well as elevated cyclin D1 expression in dKO colonic tissues. These results underscore the tumor-suppressive role of the miR-424(322)[~]503 cluster in CRC by modulating key oncogenic pathways such as MAPK and TGF{beta}. Our study provides novel insights into the interplay between PTEN loss and miRNA regulation in CRC pathogenesis.

cancer biology↗

bioRxiv2025

Multiplexed CRISPR/Cas9 Editing of Tumor Suppressor Genes Recapitulates Molecular and Morphological Features of High-Risk Endometrial Cancer

High-risk endometrial cancers (EC), such as uterine carcinosarcomas (UCS) and serous endometrial intraepithelial carcinoma (SEIC), are characterized by frequent mutations in tumor suppressor genes (TSGs) and poor clinical outcomes. Traditional genetically engineered mouse models are limited in flexibility and scalability to study the cooperative effects of multiple TSG alterations. Here, we use a multiplexed CRISPR/Cas9-based approach to simultaneously edit the top ten TSGs commonly mutated in high-risk EC directly in the mouse endometrium via intrauterine electroporation. Using rolling circle amplification (RCA) and next-generation sequencing, we demonstrate that this method induces targeted gene editing in a mosaic manner, mimicking tumor heterogeneity. We demonstrate that this approach generates histologically and molecularly faithful models of SEIC and UCS. Importantly, some edited tissues remained histologically normal, emphasizing the complex multistep nature of endometrial tumorigenesis. These CRISPR/Cas9-generated murine models serve as robust platforms to dissect the molecular underpinnings of high-risk endometrial cancer and to accelerate preclinical evaluation of novel therapeutic strategies.

cancer biology↗

bioRxiv2025

Endometrial cancer progression driven by PTEN-deficiency requires miR-424(322)~503.

Endometrial cancer is the most frequent type of cancer in the female reproductive tract. Loss-of-function alterations in PTEN, leading to enhanced PI3K/AKT activation, are among the most frequent molecular alterations in endometrial cancer. Increased PI3K/AKT signaling resulting from PTEN loss promotes cellular proliferation and confers resistance to TGF{beta}-mediated apoptosis, a key regulator of endometrial homeostasis. In this study, we have analyzed the role of miRNAs in driving these altered cellular responses. A comprehensive transcriptomic analysis of miRNA expression revealed the upregulation of several miRNAs caused by PTEN deficiency and/or TGF{beta} stimulation. The miR-424(322)[~]503 cluster drew our attention due to its involvement in regulating apoptosis and proliferation. However, miR-424(322)[~]503 cluster has a paradoxical role in cancer, exhibiting either oncogenic and tumor suppressive functions depending on cell type or context. To ascertain the function of miR-424(322)[~]503 in endometrial carcinogenesis caused by PTEN deficiency, we generated a double Pten/miR-424(322)[~]503 knock-out mice. We demonstrate that loss of miR-424(322)[~]503 impairs proliferation of both wild type or Pten deficient endometrial organoids by interfering with growth factor and PI3K/AKT signaling. Furthermore, the absence of miR-424(322)[~]503 restores TGF{beta}-induced apoptosis, which is otherwise compromised by PTEN deficiency. In vivo, Pten/miR-424(322)[~]503 knock-out mice exhibit reduced endometrial cancer progression compared to Pten deficient mice through a cell-autonomous mechanism.

cancer biology↗

bioRxiv2023

In vivo intra-uterine delivery of TAT-fused Cre recombinase and CRISPR/Cas9 editing unveil histopathology of Pten/p53-deficient endometrial cancers.

Pten and p53 are two of the most frequently mutated tumor suppressor genes in endometrial cancer. However, the functional consequences and histopathological manifestation of concomitant p53 and Pten loss of function alterations in the development of endometrial cancer is still controversial. Here, we demonstrate that simultaneous Pten and p53 deletion is sufficient to cause epithelial to mesenchymal transition phenotype in endometrial organoids. By a novel TAT-fused Cre intravaginal delivery method, we achieved local ablation of both p53 and Pten specifically in the uterus. These mice developed high-grade endometrial carcinomas and a high percentage of uterine carcinosarcomas resembling those found in humans. To further demonstrate that carcinosarcomas arise from epithelium, double Pten/p53 deficient epithelial cells were mixed with wild type stromal and myometrial cells and subcutaneously transplanted to Scid mice. All xenotransplants resulted in the development of uterine carcinosarcomas displaying high nuclear pleomorphism and metastatic potential. Accordingly, in vivo CRISPR/Cas9 disruption of Pten and p53 also triggered the development of metastatic carcinosarcomas. Our results unfadingly demonstrate that simultaneous deletion of p53 and Pten in endometrial epithelial cells is enough to trigger epithelial to mesenchymal transition that is consistently translated to the formation of uterine carcinosarcomas in vivo.

pathology↗