Biology subjects

Navaridas, R.

Publications and source records attributed to Navaridas, R..

7 recordsLinked to original sources

bioRxiv2026

A Paracrine Dietary Lipid Axis Constrains Antitumor Immunity in Liver Cancer

Overnutrition-related liver dysfunction and cancer are increasingly prevalent and highly resistant to immunotherapy. While metabolic dysregulation is a hallmark of hepatocellular carcinoma (HCC), how nutrient overload impairs antitumor immunity remains unclear. Here, we show that short-term Western diet (WD) exposure drives near-complete loss of CD8 T cell infiltration and antitumor function in HCC. We identify dietary linoleic acid (LA), the most abundant {omega}-6 fatty acid, as the dominant immunosuppressive driver. Cancer cell-restricted FADS2-mediated desaturation of LA to longer-chain {omega}-6 PUFAs drives their accumulation in the tumor interstitial fluid, suppressing infiltrating CD8 T cells via lipid peroxidation. FADS2 inhibition restores CD8 T cell function and sensitizes WD-driven HCC to PD-1-based immunotherapy. Further, the Parkinsons disease-associated deglycase DJ-1 protects LA-handling proteins from methylglyoxal-mediated glycation, sustaining tumoral immunosuppressive PUFA production. Across multiple independent human MASLD-HCC cohorts, LA metabolic activity correlates with CD8 T cell impairment, immune exclusion, and immunotherapy resistance. Overall, these studies identify a dietary lipid axis as a therapeutically actionable vulnerability in WD-associated HCC.

Cancer Biology↗

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↗

bioRxiv2024

Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway-dependent Rho/ROCK signaling.

Certain mutations can confer neomorphic gain of function (GOF) activities to the p53 protein that affect cancer progression. Yet the concept of mutant p53 GOF has been challenged. Here, using various strategies to alter the status of mutant versions of p53 in different cell lines, we demonstrate that mutant p53 stimulates cancer cell invasion in three-dimensional environments. Mechanistically, mutant p53 enhances RhoA/ROCK-dependent cell contractility and cell-mediated extracellular matrix (ECM) re-organization via increasing mevalonate pathway-dependent RhoA localization to the membrane. In line with this, RhoA-dependent pro-invasive activity is also mediated by IDI-1, a mevalonate pathway product. Further, the invasion-enhancing effect of mutant p53 is dictated by the biomechanical properties of the surrounding ECM, thereby adding a cell-independent layer of regulation to mutant p53 GOF activity that is mediated by dynamic reciprocal cell-ECM interactions. Together our findings link mutant p53 metabolic GOF activity with an invasive cellular phenotype in physiologically relevant and context-dependent settings. SignificanceThis study addresses the contribution of mutant p53 to the process of cancer cell dissemination in physiologically relevant three-dimensional environments - a key characteristic of metastatic disease. Several mutant p53 proteins display pro-oncogenic activity with respect to cancer cell invasion in 3D environments via mevalonate pathway-dependent Rho/ROCK signaling axis.

cancer biology↗

bioRxiv2024

Multiple endocrine defects in adult-onset Sprouty1/2/4 triple knockout mice

Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinases, especially of Ret and the FGF receptors. As such, they play distinct and overlapping roles in embryo morphogenesis and are considered to be tumor suppressors in adult life. Genetic experiments in mice have defined in great detail the role of these genes during embryonic development, however their function in adult mice is less clearly established. Here we generate adult-onset, whole body Spry1/2/4 triple knockout mice. Tumor incidence in triple mutant mice is comparable to that of wild type littermates of up to one year of age, indicating that Sprouty loss per se is not sufficient to initiate tumorigenesis. On the other hand, triple knockout mice do not gain weight as they age, show less visceral fat, and have lower plasma glucose levels than wild type littermates, despite showing similar food intake and slightly reduced motor function. They also show alopecia, eyelid inflammation, and mild hyperthyroidism. Finally, triple knockout mice present phosphaturia and hypophosphatemia, suggesting exacerbated signaling downstream of FGF23. In conclusion, triple knockout mice develop a series of endocrine abnormalities but do not show increased tumor incidence.

physiology↗

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↗