Biology subjects

Rubio, C.

Publications and source records attributed to Rubio, C..

4 recordsLinked to original sources

bioRxiv2025

KCNK18 c.1107del frameshift in peripheral neuropathy links TRESK dysfunction to neuropathic pain

Neuropathic pain is commonly accompanied by hyperexcitability of nociceptive neurons, which is driven by regulation of several ion channels, including two-pore domain potassium channels (K2P) that stabilize the resting membrane potential. The TWIK-Related Spinal cord potassium channel (TRESK, K2p18.1) is predominantly expressed in sensory ganglia, where it provides major background K conductance. We describe a heterozygous c.1107del frameshift mutation in KCNK18, encoding TRESK, found in a patient with painful small fiber neuropathy and dysautonomia. This C-terminal c.1107del mutant is predicted to generate an elongated C-terminal domain, with an altered protein sequence. Whole-cell patch calmp recordings showed that the c.1107del variant reduced K current density, while heterozygous-like expression resulted in intermediate currents, consistent with a haploinsufficiency mechanism. Confocal imaging revealed decreased plasma membrane expression, indicating a trafficking-dependent loss of function while oligomerization with TRESK (homomeric channels) or TREK1 remained intact. In silico analysis revealed an altered phosphorylation pattern and reduced C-terminal hydrophobicity in the mutant TRESK. Overall, these findings support c.1107del as a pathogenic KCNK18 variant causing TRESK haploinsufficiency, offering mechanistic insight into the pathophysiology of neuropathic pain.

neuroscience↗

bioRxiv2025

CD44v6 Drives Tumor Aggressiveness and Chemoresistance in Bladder Cancer

Bladder cancer is a fast-moving and recurrent malignancy where survival hinges on early detection and precise risk stratification. The search for robust biomarkers is urgent, and CD44v6 has emerged as a compelling candidate. In this study, we reveal that CD44v6 is not merely a marker but a driver of urothelial carcinoma aggressiveness. Through integrated clinical and functional analyses, we show that high CD44v6 expression is strongly associated with poor patient outcomes. Mechanistic investigations demonstrate that CD44v6 amplifies the proliferative, migratory, and invasive potential of bladder cancer cells, while conferring marked resistance to cisplatin. These findings position CD44v6 at the intersection of tumor progression and therapeutic failure, underscoring its value as both a prognostic biomarker and a promising therapeutic target. Targeting CD44v6 could pave the way for strategies that curb disease aggressiveness and overcome chemoresistance in bladder cancer.

cancer biology↗

bioRxiv2025

Cell-of-origin and genetic drivers define advanced bladder cancer subtypes and potential therapeutic response in mouse models

Bladder cancer (BC) remains a major clinical challenge owing to its high recurrence, limited treatment options, and molecular heterogeneity. Despite recent therapeutic advances, prognosis remains poor, and resistance is frequent, underscoring the need for improved experimental models to study tumorigenesis and therapeutic response. A key limitation of advanced BC research is the scarcity of in vivo models that accurately reflect invasive disease, with even fewer capturing the complexity of metastasis. To investigate how the cell-of-origin and specific combinations of driver mutations influence in bladder tumorigenesis, we developed and characterized four genetically engineered mouse models of advanced BC by targeting two combinations of tumor suppressor genes (Pten and Trp53, or Pten, Trp53, Rb1, and Rbl1) in basal or suprabasal urothelial cells through intravesical of Cre-adenovirus delivery. Loss of the retinoblastoma family reduced cancer-specific survival and was associated with more differentiated carcinomas. In both genetic backgrounds, luminal-derived tumors developed earlier but showed fewer metastatic events. Histopathological and transcriptomic analyses revealed that these tumors resemble human basal-squamous and stroma-rich subtypes, sharing regulatory networks and activated signaling pathways with human invasive tumors. Notably, tumors lacking retinoblastoma family genes exhibited increased immune infiltration, reinforcing the value of these models for diverse preclinical applications. To overcome detection and latency limitations, we established tumor-derived cell lines and generated syngeneic graft models. These were validated as preclinical platforms, exhibiting therapeutic responses to CDK4/6 inhibition and anti-PD-L1 immunotherapy. Our findings highlight the value of these novel models for studying BC progression and evaluating emerging therapeutic strategies in immunocompetent settings.

cancer biology↗

bioRxiv2023

Comprehensive Landscape of Non-muscle Invasive Bladder Cancer Tumour Microenvironment and Prognostic value of Cancer-Associated Myofibroblasts

BACKGROUNDNon-muscle-invasive bladder cancer (NMIBC) poses clinical challenges due to its high recurrence and progression rates. While Bacillus Calmette-Guerin (BCG) remains as the gold standard treatment for high-risk NMIBC, recent irruption of anti-PD-1/PD-L1 drugs claims for a comprehensive understanding of the tumour microenvironment (TME) of these tumors. METHODSThe present prospective study consisted on the analysis 98 fresh NMIBC samples, tumor and non-pathological tissue, via flow cytometry. Final analysis included distribution of 11 cell types and the expression of PD-L1 in 66 tumor and 62 non-pathological tissue biopsies from 73 NMIBC patients (84.4% paired samples). The results were validated using publicly available transcriptomic data, and histology. RESULTSIn comparison to non-pathological tissue, the TME of NMIBC presented microvascular alterations, increased cancer-associated fibroblast (CAF) and myofibroblast (myoCAF) presence, and varied immune cell distribution. Heterogeneous PD-L1 expression was observed across subsets, with cancer cells as primary potential anti-PD-L1 binding targets. Unbiased analysis revealed that myoCAF and M2-like macrophages are enriched in high grade NMIBC tumors, but only myoCAF were associated with higher rates of progression and recurrence, as we confirmed in three independent transcriptomic cohorts (888 total patients). We further validated the prognostic value of myoCAFs by tissue micro-array. CONCLUSIONThis comprehensive analysis provides a roadmap to establish the full landscape of the NMIB[C]s TME, highlighting myoCAFs as potential prognostic markers. FUNDINGThis study was funded by FC AECC (INVES222946GARC), Consejeria de Educacion, Ciencia y Universidades de la CAM (2018-T2/BMD-10342), Hoffmann-La Roche, Ministerio de Ciencia e Innovacion (INMUNOEPIBLA) and ISCIII/FEDER (CIBERONC CB16/12/00489)

cancer biology↗