Biology subjects

Carnero, A.

Publications and source records attributed to Carnero, A..

4 recordsLinked to original sources

bioRxiv2026

Tumoral Switch in NUMB splicing changes essential transcription pathways and induces malignant properties in tumour cells

BackgroundRecent evidence suggests that cancer can exhibit splicing alterations that give rise to tumour-specific isoforms. One example is NUMB, which produces four isoforms (p72, p71, p66, and p65) through alternative splicing of exons 3 and 9. Traditionally considered a tumour suppressor, it also has been considered an oncogene. We propose that this duality is due to isoform-specific expression. ResultsUsing public databases, we identified a tumour-associated switch in NUMB isoform expression: p72/p71 are upregulated in tumours, whereas p66/p65 are more expressed in non-tumour tissues. These isoforms correlate differently with cellular processes. NUMBL, a NUMB homolog, behaves similarly to p65. We identified two transcriptional clusters: one characterized by high expression of p72/p71, and another by p66/p65/NUMBL. Each group was associated differently with the Notch, WNT/{beta}-catenin, Hedgehog, and Hippo signalling pathways, suggesting isoform-specific regulatory roles. Analysis of breast cancer cell lines (CCLE) led to a NUMB score based on isoform expression, which classified cell lines into biologically distinct groups. The p72/p71-enriched group showed distinct signatures, pathway activity, and drug sensitivity. Applying this score to TCGA-BRCA samples revealed a significant link between high NUMB-score and poor survival, confirmed by Kaplan-Meier analysis. ConclusionsNUMB emerges as a potential oncogenic contributor and biomarker in splicing-based personalised medicine, highlighting isoform-specific expression as a clinically relevant determinant of tumour behaviour, pathway activity, and therapeutic response.

cancer biology↗

bioRxiv2025

HOOK2 downregulation compromises the tumorigenic and stemness properties of ovarian cancer cells by increasing endoplasmic reticulum stress

Ovarian cancer stands out as one of the tumors with a high mortality rate in women. Therefore, the search for new therapeutic targets is essential to enhance patient prognosis. There is evidence suggesting that Hook2, an adaptor protein involved in microtubule transport, may play a role in cancer, particularly ovarian cancer. This study examines the role of HOOK2 in the progression of ovarian tumors. The findings reveal that a decrease in HOOK2 levels leads to diminished growth and cellular migration in ovarian cancer cells, impeding the in vivo formation of tumors. The reduction of HOOK2 is associated with both an increase in endoplasmic reticulum stress and an elevation in cell death, the latter likely caused by the activation of the unfolded protein response. Moreover, the study observes that the decrease in HOOK2 diminishes the properties of cancer stem cells in ovarian cancer, possibly due to the increase in cell death specifically found within these stem cells. Given the profound impact of reduced HOOK2 levels on ovarian cancer cells, this gene emerges as a promising therapeutic strategy for treating ovarian cancer patients.

cancer biology↗

bioRxiv2023

Essential role of PLD2 in hypoxia-induced stemness and therapy resistance in ovarian tumors

Hypoxia in solid tumors is a source of chemoresistance that determines poor patient prognosis and relies on the presence of cancer stem cells (CSCs). Here we use ovarian cancer (OC) as a model and a combination of 2D and 3D cell cultures, xenograft models, patient samples, transcriptional databases, iPSCs and ATAC-seq, to address the mechanisms leading to hypoxia-induced CSC generation and chemoresistance. We show that hypoxia activates the expression of the PLD2 gene encoding phospholipase D2. PLD2 overexpression leads to increased CSC-like features, similar to hypoxia, while PLD2 depletion in hypoxia partially suppresses these effects, indicating a role of PLD2 in hypoxia-induced CSC generation in OC. Finally, PLD2 overexpression provokes chemoresistance that is suppressed by combination treatment with PLD2 inhibition. Altogether, our work highlights the HIF-1D-PLD2 axis in hypoxia-induced CSC generation and chemoresistance in OC and proposes an alternative treatment for patients with high PLD2 expression. Statement of SignificanceHypoxia in solid tumors is a major source of chemoresistance and cancer stem cells. We show that hypoxia-induced stemness is mediated by phospholipase D2 in ovarian tumors, generating therapy resistance that is overcome by phospholipase D inhibition. Therefore, we propose an alternative treatment for patients with high PLD2 expression.

cancer biology↗

bioRxiv2021

Identification of a minimal biomarker profile in head-and-neck squamous cell carcinoma tumors

Although important advances have been made in the knowledge of the molecular mechanisms leading to the development, of head and neck squamous cell carcinoma (HNSCC), only PDL1 is used for the immunotherapy (pemborlizumab) treatment in the first line of metastatic or recurrent disease. There are no other molecular biomarkers currently used in clinical practice. The objective of the study was to identify transcriptional alterations in patients with oral cavity cancer that identify gene networks responsible for resistance to treatment and prognosis. To identify possible targets for the treatment or prevention of these tumors, we screened for changes in transcription of genes that were recurrently altered in patients and that successfully stratify tumoral and non-tumoral samples, as well as patient survival, based on expression levels. The gene panels are primarily related to the cell cycle, DNA damage response, cytokine signaling and the immune system but also to the embryonic stem cell core. Validation of these panels in an independent cohort led to the identification of three non-interconnected genes, WDR66, SERPINH1 and ZNF622, that can predict patient survival and are differentially expressed in 3D cultures from HNSCC primary cell lines. These genes are related to stemness phenotype are transcriptional targets of the pluripotency transcription factors Sox2 and c-Myc. Our results suggest that WDR66, SERPINH1 and ZNF622 con-stitute a minimal signature of stemness transcriptional targets able to predict the prognosis of HNSCC tumors. Simple SummaryThe objective of the study was to identify transcriptional alterations in patients with oral cavity cancer to possibly identify gene networks responsible for resistance to treatment and prognosis. We identify bioinformatically gene panels are primarily related to the cell cycle, DNA damage response, cytokine signaling and the immune system but also to the embryonic stem cell core. Validation of these panels in patients independent cohorts led to the identification of three non-interconnected genes, WDR66, SERPINHl and ZNF622, that can predict patient survival and are differentially expressed in cancer stem cells cultures from HNSCC. These genes are related to stemness phenotype and epithelial-to-mesenchymal transition and are transcriptional targets of the pluripotency transcription factors Sox2 and c-Myc.

cancer biology↗