Biology subjects

Vergara, M.

Publications and source records attributed to Vergara, M..

6 recordsLinked to original sources

bioRxiv2026

Genomic analysis of BCG unresponsive non-muscle-invasive bladder cancer identifies drivers of sensitivity to intravesical Gemcitabine/Docetaxel

Background and ObjectivesIntravesical gemcitabine/docetaxel (Gem/Doce) is an effective therapy for Bacillus Calmette- Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC), achieving 50% complete responses at 2 years. However, the genomic determinants underlying response and resistance to Gem/Doce remain poorly defined. Our objective was to define the mutational landscape of BCG-unresponsive NMIBC and nominate genomic features associated with response or resistance Gem/Doce. MethodsPatients with BCG-unresponsive NMIBC treated with Gem/Doce were classified as responders (recurrence-free survival [RFS] >12 months) or non-responders (RFS <12 months). Whole-exome sequencing was performed on tumors prior to Gem/Doce treatment (n=23). Single nucleotide variants were identified and annotated using a Cancer Genome Analysis pipeline. Copy number alterations were inferred with ABSOLUTE, and clonal architecture was reconstructed using PhylogicNDT. Key Findings and LimitationsResponders demonstrated significantly prolonged time to high-grade recurrence (3.5 vs 42 months, p<0.001) and cystectomy compared with non-responders (9.5 months vs not reached; p<0.001). Non-responders exhibited higher tumor mutational burden (13.66 vs 8.71; p=0.02) and more frequent whole-genome doubling (2/2 non-responders vs 0/1 responders; p=0.33). Phylogenetic analyses revealed clonal BAP1 and subclonal BRCA2 mutations in responders, whereas non-responders harbored clonal FGFR3 mutations. Limitations include small sample size and retrospective design. Conclusions and Clinical ImplicationsDistinct genomic features underlie differential response to Gem/Doce in BCG-unresponsive NMIBC. In responders, alterations in DNA repair pathways (e.g., BRCA2) may sensitize tumors to chemotherapy, while non-responders with FGFR3 mutations may benefit from alternative targeted strategies. These findings warrant validation in larger cohorts and support the development of biomarker-driven clinical trials. Patient summaryIn this report we analyzed bladder tumors and found that some tumors respond well to treatment because they have defects in repairing DNA, making them more vulnerable to chemotherapy. In contrast, tumors that do not respond to chemotherapy harbor different genetic changes that help them survive and grow. These findings may help physicians choose more effective and personalized treatments in the future.

genomics↗

bioRxiv2026

Habitat specialization shapes the evolution of transcriptional responses to hypoxia

Oxygen limitation is a widespread environmental constraint that shapes physiological and evolutionary responses across ecosystems. A central unresolved question is whether tolerance to hypoxia reflects generalized stress responses or coordinated regulatory strategies shaped by long-term environmental exposure. Here, we use comparative transcriptomic analyses to examine gene expression responses to low oxygen in two aquifer-dwelling stoneflies (Isocapnia sp. and Paraperla frontalis) and one benthic species (Sweltsa sp.) under controlled conditions. Time-series analysis in Isocapnia sp. revealed a multi-phase transcriptional response involving early regulatory activation, metabolic reorganization, and late-stage cellular stabilization. Across aquifer taxa, hypoxia was associated with downregulation of energy-demanding processes and upregulation of pathways related to oxidative stress mitigation, metabolite transport, and protein folding, consistent with coordinated cellular adjustment to oxygen limitation. In contrast, the river benthic species exhibited transcriptional profiles dominated by neural signaling, ion channel activity, and structural remodeling, which are patterns consistent with acute physiological stress rather than coordinated regulation. Despite these differences, all taxa showed modulation of ion transport and calcium signaling pathways, suggesting conserved mechanisms of hypoxia sensing. Together, these results indicate that transcriptional responses to hypoxia differ systematically with habitat and are consistent with the evolution of distinct regulatory strategies in chronically hypoxic environments. Significant statementOxygen limitation is a common environmental challenge that affects organisms across aquatic and terrestrial ecosystems, yet the mechanisms by which species cope with low oxygen remain incompletely understood. A key question is whether tolerance to hypoxia reflects common stress responses or the evolution of coordinated metabolic regulatory strategies under chronic exposure. By comparing gene expression responses in closely related aquatic insects from oxygen-variable underground aquifers and oxygen-rich river habitats, we show that species that evolved under persistent hypoxia exhibit transcriptional patterns consistent with energy conservation and cellular stabilization, whereas those experiencing hypoxia as a transient stress display signature of physiological disruption. These findings highlight fundamental differences between evolutionarily adaptive and acute stress-driven responses to environmental change and provide insight into how organisms may respond to increasing hypoxia under global change.

ecology↗

bioRxiv2025

Myc and Kras cooperate in adult acinar cells to drive phenotypic heterogeneity, metastasis, and therapeutic resistance in a novel pancreatic cancer mouse model

Pancreatic ductal adenocarcinoma (PDAc) is a deadly malignancy, most commonly diagnosed in advanced stages when no curative treatments are available. The development of new models that aid ongoing investigation into the mechanisms by which it initiates, disseminates, and evades treatment is of the utmost importance. In vivo models that accurately recapitulate the features and spectrum of human pancreatic cancer are paramount to make a dent in this disease as two decades of the standard-of-care have failed to substantially improve survival. Here, we take advantage of our finding that post-translational stabiliziation of MYC downstream of the canonical PDAc driver, mutant KRAS, is an early event in PDAc progression to design a novel mouse model of PDAc progression based on deregulated, constituitive expression of Myc and mutant Kras in adult pancreatic acinar cells. Tumors from this KMC model histologically and molecularly recapitulate heterogeneity seen in human PDAc, with a high rate of metastasis to the liver. Cell lines derived from KMC autochthonous PDAc provide new models for orthotopic primary tumors that reliably metastasize to the liver and lung, providing important new tools to efficiently study the metastatic cascade and aid in the develoment of new therapeutics addressing metastatic disease. Cell lines represent distinct molecular subtypes with corresponding differential drug sensitivity. Toghether, this model provides a new and additional tool in the study of pancreatic cancer and the means by which it so deftly evades our best efforts at treatment.

cancer biology↗

bioRxiv2025

ADAR1 regulates alternative splicing through an RNA editing-independent mechanism.

Adenosine-to-inosine (A-to-I) RNA editing and alternative splicing occur co-transcriptionally and can regulate and influence each other. The RNA editing enzymes ADAR1 and ADAR2 catalyze A-to-I RNA editing, where it has been shown that expression changes in both RNA editing enzymes exert alternative splicing. ADAR1 manipulation has a significant impact on alternative splicing. While many of those changes are related to changes in their A-to-I RNA editing activity, we speculate that ADAR1 may also influence splicing in an editing-independent manner. In this work, the protein-protein interactome of ADAR1 revealed that ADAR1 interacts with spliceosome co-factors and auxiliary splicing regulators. We confirmed that ADAR1 does not only influence splicing through editing but also throughout editing-independent functions with even greater penetrance. We show that ADAR1 modulates the splicing of transcripts encoding splicing factors, with many of these splice sites overlapping with known splicing changes induced by the splicing factor ACIN1, suggesting indirect effects upon ADAR1 expression. In summary, we show that ADAR1 can regulate splicing in an editing-independent manner, which likely occurs by widespread alteration of the splicing factor isoform landscape.

molecular biology↗

bioRxiv2023

Asymmetric control of food intake by left and right vagal sensory neurons

We investigated the lateralization of gut-innervating vagal sensory neurons and their roles in feeding behavior. Using genetic, anatomical, and behavioral analyses, we discovered a subset of highly lateralized vagal sensory neurons with distinct sensory responses to intestinal stimuli. Our results demonstrated that left vagal sensory neurons (LNG) are crucial for distension-induced satiety, while right vagal sensory neurons (RNG) mediate preference for nutritive foods. Furthermore, these lateralized neurons engage different central circuits, with LNG neurons recruiting brain regions associated with energy balance and RNG neurons activating areas related to salience, memory, and reward. Altogether, our findings unveil the diverse roles of asymmetrical gut-vagal-brain circuits in feeding behavior, offering new insights for potential therapeutic interventions targeting vagal nerve stimulation in metabolic and neuropsychiatric diseases. One Sentence SummaryLateralized gut-brain circuits respond to different sensory modalities and control distinct feeding behaviors.

neuroscience↗

bioRxiv2022

Labeled lines for fat and sugar reward combine to promote overeating

Food is a powerful natural reinforcer that guides feeding decisions. The vagus nerve conveys internal sensory information from the gut to the brain about nutritional value; however, the cellular and molecular basis of macronutrient-specific reward circuits are poorly understood. Here, we monitor in vivo calcium dynamics to provide direct evidence of independent vagal sensing pathways for detection of dietary fats and sugars. Using activity-dependent genetic capture of nutrient-specific vagal neurons activated in response gut infusions, we demonstrate the existence of separate hard-wired reward circuits for fat and sugar that are necessary and sufficient for nutrient-specific reinforcement. Even when controlling for calories, combined activation of fat and sugar circuits increases overeating compared to fat or sugar alone. This work provides new insight on the complex sensory circuitry that mediates motivated behavior and suggests that a subconscious internal drive to consume obesogenic diets (e.g., those high in both fat and sugar) may impede conscious dieting efforts.

neuroscience↗