Biology subjects

Mosquera, J.

Publications and source records attributed to Mosquera, J..

3 recordsLinked to original sources

bioRxiv2026

Dual Role of Cx43 in Enhancing CDK4/6 Inhibitor Response and Promoting the Elimination of Therapy-Induced Senescent Tumor Cells

Breast cancer has become the most prevalent malignancy worldwide. A key clinical advance has been the introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), that in combination with endocrine therapy has been a major advance for the treatment of luminal (ER/HER2-) breast cancer. CDK4/6i induce cell cycle arrest in G1 and cellular senescence improving clinical outputs. However, limited efficacy and therapeutic resistance remain major challenges due to incomplete effects or the failure to eliminate the accumulated tumor senescent cells. Here, we identify connexin 43 (Cx43), a membrane channel protein involved in cell-to-cell communication, identified as a novel target in luminal breast cancer that potentiates the effects of CDK4/6 inhibitors. We found that Cx43 not only reduces tumor cell proliferation by enhancing senescence but also reshapes the Senescence-Associated Secretory Phenotype (SASP) profile. We also demonstrate that, in combination with CDK4/6i, Cx43 reinforces G1 arrest via transcriptional downregulation of E2F targets including CDK4 and CDK6, and through interaction with p21/p27, deepens the senescent state. Importantly, the Cx43-associated senescent phenotype sensitizes tumor cells accumulated under CDK4/6i treatment to the senolytic agent Navitoclax. Our results demonstrate that upregulation of Cx43 in breast cancer reduces proliferation and enhances the clearance of therapy-induced senescent cells. The triple-drug strategy comprising CDK4/6i, Cx43 delivery, and a senolytic drug such as Navitoclax holds great promise for overcoming CDK4/6i resistance and improving clinical outcomes in ER/HER2- breast cancer and may also be applicable to other cancer types that respond to CDK4/6i or other pro-senescence antitumoral drugs.

cancer biology↗

bioRxiv2025

Incentive Salience, not Psychomotor Sensitization or Tolerance, Drives Escalation of Cocaine Self-Administration in Heterogeneous Stock Rats

Sensitization and tolerance are two phenomena often studied independently despite overlapping neurobiological substrates. Each has extensive research showing their influence on the development and maintenance of addiction, but the degree to which they drive escalation in cocaine self-administration is poorly understood. Using self-administration, intravenous noncontingent infusions, and pose-estimation machine vision, we find that incentive salience, not psychomotor sensitization or tolerance, drives the escalation of cocaine self-administration in heterogenous stock rats. Individual differences in psychomotor sensitization or tolerance were found to have no effect on cocaine intake. Incentive salience as measured by locomotion and active lever entrances per meter traveled occurring before the self-administration session began (pre-lever activity measures) during Short Access (2-hours) was found to predict intake during Long Access (6-hours). Both pre-lever locomotion and active lever entrances per meter were found to increase during Long Access and after two-to-three days of abstinence. Critically, rats with low pre-lever activity during Short Access escalated both their intake and pre-lever measures by the end of Long Access to levels comparable with high pre-lever activity rats who maintained their elevated responding. These findings support the notion that incentive salience during Short Access is a catalyst to escalated use and an early marker of addiction vulnerability. Moreover, they suggest that individuals initially resistant to incentive salience can, with sufficient exposure, become sensitized and escalate cocaine use to the same level as more susceptible individuals. Analysis of pre-lever activity offers a novel longitudinal behavioral marker to predict vulnerability and provides a framework for understanding individual trajectories of addiction.

neuroscience↗

bioRxiv2025

Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats

BackgroundCocaine use disorder (CUD) is a major public health crisis with detrimental individual and societal effects. The specific genes mediating CUD remain largely unknown. MethodsWe conducted a genome-wide association study (GWAS) using outbred N/NIH Heterogeneous Stock (HS; n = 836, female = 415, male = 421) rats. We examined multiple CUD-related phenotypes that captured acquisition of self-administration, escalation of intake, and compulsive-like responding. ResultsConsistent with the existing literature, these traits were phenotypically and genetically correlated and exhibited modest heritability (h2 = 0.07 - 0.16). We identified six genome-wide significant associations. One locus on chromosome 19 was associated with the variable time between cocaine infusions (post infusion interval) and contains several carboxylesterase genes that are orthologous to the human CES1 gene; notably, carboxylesterases metabolize cocaine. Three non-synonymous coding variants in the genes Ces1c and Ces1d were in perfect linkage disequilibrium with this locus, suggesting that one or more of them might be the causal SNP. The other 5 loci also contained promising coding and expression variants, including Trak2, a gene previously associated with CUD in human GWAS and Slc10a7, Plcl1, and Satb2 which have been associated with alcohol and tobacco use disorder. ConclusionsThis is the largest genetic study of cocaine self-administration ever conducted in any species. Our results replicate previous loci associated with CUD in humans and provide several novel biological insights including the potential of pharmacological strategies targeting carboxylesterases for the treatment of CUD.

genetics↗