About

Nicholas Webster is a faculty member associated with the Division of Endocrinology & Metabolism at UC San Diego School of Medicine. His research focuses on clinical diabetes, specifically studying medications as adjunct therapies to insulin in Type 1 Diabetes to improve blood glucose control, promote weight loss, and decrease the risks of diabetic ketoacidosis (DKA) and cardiovascular complications. He is part of the Clinical Diabetes Research Group, which specializes in cutting-edge treatments and technologies for both type 1 and type 2 diabetes, collaborating as one of only 16 U.S. research centers established by the National Institute of Diabetes and Digestive and Kidney Diseases to accelerate basic and clinical research in diabetes.

Research topics

• Internal medicine
• Medicine
• Endocrinology
• Biology
• Cell biology
• Cancer research
• Genetics
• Immunology

Selected publications

• Catestatin peptide impedes melanoma progression and drug resistance by reprogramming oncogenic signaling pathways

  Oncogenesis · 2026-05-21

  articleOpen access

  Melanoma remains one of the most aggressive and therapy-resistant cancers, underscoring the need for innovative therapeutic strategies. In our current study we report a peptide-based approach as potential therapeutic. Here we report for the first time the involvement of Catestatin (CST) peptide in carcinogenesis, with melanoma identified as unexplored and therapeutically relevant context. The expression and role of CST, a Chromogranin A (CgA)-derived peptide with immunomodulatory and reparative properties in skin injury, led us to examine its connection to melanoma. Analysis of human melanoma tissues revealed that CST expression decreases with advancing disease stage, suggesting a potential tumor-suppressive function. Restoration of CST in patient-derived melanoma cells and established melanoma cell lines (A375, B16F10, and SKMEL28) induced apoptosis and suppressed proliferation and migratory capacity, while normal skin fibroblasts remained unaffected, indicating tumor-selective activity. In vivo, CST administration significantly reduced tumor growth and tumor weight in the B16F10 melanoma mouse model, with no detectable systemic toxicity. Transcriptomic profiling of CST-treated melanoma cells and tumors revealed downregulation of pathways involved in hypoxia signaling, extracellular-matrix remodeling, epithelial-to-mesenchymal transition (EMT), and stress-adaptive responses, key drivers of melanoma invasion and progression. Consistent with these findings, CST suppressed several mediators of tumor progression. CST also reduced the viability and migration of Vemurafenib-resistant A375 cells, accompanied by the downregulation of multiple resistance-associated genes. Together, these findings establish catestatin as a novel regulator of melanoma growth and therapeutic resistance and provide a mechanistic rationale for the development of CST-based peptide therapeutics targeting both treatment-naive and drug-resistant melanoma.Catestatin Suppresses Tumor Progression and Metastasis by Inducing Apoptosis and Inhibiting Pro-tumorigenic Signaling. Catestatin (CST), a Chromogranin A-derived peptide, exhibits potent anti-tumor activity by suppressing cancer progression across multiple stages. CST levels decline with advancing tumor stage, suggesting a loss of endogenous tumor restraint during progression to metastasis. In patient-derived melanoma cells and tumor models (A375 and B16F10), CST treatment induces apoptotic cell death. Mechanistically, CST downregulates key pro-tumorigenic and pro-fibrotic signaling molecules, including LOXL2, PDGFRB, CCN2, and DDIT4, which are associated with extracellular-matrix remodeling, growth factor signaling, and cellular stress adaptation. These findings identify CST as a novel regulator of tumor survival and metastatic potential, supporting its therapeutic potential as a peptide-based anti-cancer agent.

  PublisherOA PDFDOI

• Multi-omics profiling reveals microenvironmental remodeling as a key driver of house dust mite-induced lung cancer progression

  Neoplasia · 2026-01-28

  articleOpen access

  • Chronic house dust mite (HDM) exposure accelerates lung tumor growth through non-mutagenic, immune-mediated mechanisms. • HDM activates pro-inflammatory and immune programs in normal lung tissue but suppresses antitumor T cell responses in tumors. • Multi-omics profiling reveals epigenetic silencing of immune genes and a myeloid-enriched, lymphoid-deficient tumor microenvironment. • HDM-driven tumor promotion depends on IL-17A but not IL-1β, establishing IL-17A as a central driver of lung tumor promotion. Chronic exposure to the common aeroallergen house dust mite (HDM) induces lung inflammation and DNA damage, but its impact on lung cancer development remains largely unexplored. Using whole-genome sequencing, RNA-seq, and DNA methylation profiling, we assessed HDM effects in lung epithelial cell lines and a mouse orthotopic lung cancer model. HDM accelerated tumor growth without altering mutational burden. Transcriptomic and epigenetic analyses revealed tissue-specific effects: in normal lung, HDM enhanced pro-inflammatory and immune activation programs, whereas in tumors it suppressed T cell responses, antigen presentation, and chemokine signaling. Immune deconvolution showed a shift toward myeloid enrichment and lymphoid suppression, with reduced cytotoxic T and NK signatures. Notably, HDM-driven tumor promotion was abolished in Il17a −/− but not Il1b −/− mice, identifying IL-17A as a critical mediator. These findings demonstrate that chronic aeroallergen exposure reshapes the lung microenvironment to promote immune suppression and accelerate lung cancer progression.

  PublisherDOI

• SRSF3-TRIM28-MDC1 prevents DNA damage caused by R-loops in fatty liver disease in mice

  JCI Insight · 2026-01-01

  articleOpen accessSenior author

  Serine-rich splicing factor 3 (SRSF3) is crucial for the metabolic functions of the liver. The genetic deletion of SRSF3 in mouse hepatocytes impairs hepatic lipid and glucose metabolism and leads to fibrosis and formation of hepatocellular adenoma that progresses to hepatocellular carcinoma. SRSF3 protein is proteosomally degraded in metabolic-dysfunction associated fatty liver disease (MAFLD) and metabolic-dysfunction-associated steatohepatitis (MASH). We show here that depleting SRSF3 protein in hepatocytes promoted R-loop accumulation and increased DNA damage in the liver. Prevention of SRSF3 degradation in vivo protected hepatocytes from DNA double-strand breaks in mice with MASH. This protection extended to other DNA-damaging agents such as camptothecin, palmitic acid, or hydrogen peroxide when tested on HepG2 cells in vitro. SRSF3 interacted with TRIM28 and MDC1, which are components of the ATM DNA-damage repair complex, and knockdown of any of these 3 proteins reduced the expression of the other 2 proteins, suggesting they form a functional complex. Lastly, by preventing degradation of SRSF3, we were able to reduce tumors in a diethyl-nitrosamine-induced (DEN-induced) model of cirrhotic HCC. These findings suggest that maintenance of SRSF3 protein stability is crucial for preventing DNA damage and protecting liver from early metabolic liver disease and progression to HCC.

  PublisherDOI

• Multi-omics profiling reveals microenvironmental remodeling as a key driver of house dust mite-induced lung cancer progression

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-29

  preprintOpen access

  Summary Chronic exposure to the common aeroallergen house dust mite (HDM) induces lung inflammation and DNA damage, but its impact on lung cancer development remains largely unexplored. Using whole-genome sequencing, RNA-seq, and DNA methylation profiling, we assessed HDM effects in lung epithelial cell lines and a mouse orthotopic lung cancer model. HDM accelerated tumor growth without altering mutational burden. Transcriptomic and epigenetic analyses revealed tissue-specific effects: in normal lung, HDM enhanced pro-inflammatory and immune activation programs, whereas in tumors it suppressed T cell responses, antigen presentation, and chemokine signaling. Immune deconvolution showed a shift toward myeloid enrichment and lymphoid suppression, with reduced cytotoxic T and NK signatures. Notably, HDM-driven tumor promotion was abolished in Il17a −/− but not Il1b −/− mice, identifying IL-17A as a critical mediator. These findings demonstrate that chronic aeroallergen exposure reshapes the lung microenvironment to promote immune suppression and accelerate lung cancer progression. Highlights Chronic house dust mite (HDM) exposure accelerates lung tumor growth through non-mutagenic, immune-mediated mechanisms. HDM activates pro-inflammatory and immune programs in normal lung tissue but suppresses antitumor T cell responses in tumors. Multi-omics profiling reveals epigenetic silencing of immune genes and a myeloid-enriched, lymphoid-deficient tumor microenvironment. HDM-driven tumor promotion depends on IL-17A but not IL-1β, establishing IL-17A as a central driver of lung tumor promotion.

  PublisherOA PDFDOI

• Catestatin suppresses melanoma progression and drug resistance through multitargeted modulation of signaling pathways

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-24

  preprintOpen access

  Background: Despite advances in targeted and immune-based therapies, melanoma remains one of the most aggressive and treatment-resistant cancers. Resistance to small-molecule inhibitors and immune checkpoint blockade highlights the need for new mechanistically distinct interventions. Catestatin (CST), a Chromogranin A (CgA)-derived peptide with immunomodulatory and reparative properties, has been implicated in tissue protection, but its role in melanoma remains unknown. Methods: CST expression was analyzed across melanoma stages and correlated with disease progression. Functional effects of CST were assessed in patient-derived and established melanoma cell lines, as well as in B16-F10 melanoma-bearing mice. RNA sequencing and pathway analyses were performed to delineate CST-regulated molecular networks. Vemurafenib-resistant A375 cells were used to examine CST's effects on drug resistance mechanisms. Results: , systemic CST administration significantly reduced tumor volume and mass. Transcriptomic profiling revealed coordinated downregulation of hypoxia-inducible, epithelial-mesenchymal transition (EMT), and collagen-remodeling pathways, alongside suppression of oxidative stress-adaptive signaling. In Vemurafenib-resistant A375 cells, CST restored apoptotic sensitivity and repressed multiple MAPK and PI3K-AKT-linked resistance genes. Conclusions: CST acts as a mechanistically distinct peptide modulator that reprograms oncogenic signaling through inhibition of hypoxia, EMT, and survival pathways. These findings identify CST as a promising therapeutic prototype for mitigating melanoma progression and overcoming resistance to targeted therapy.

  PublisherOA PDFDOI

• SRSF3 is oncogenic in breast but tumor-suppressive in liver by differential regulation of gene expression

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-17 · 1 citations

  preprintOpen access

  SRSF3 (SRp20) is an essential splicing factor. We discovered Srsf3 plays an oncogenic role in breast cancer and Srsf3 knockout (KO) in mammary glands delays the development of breast cancer in an Erbb2 mouse model. In contrast, Srsf3 is tumor-suppressive in mouse liver tissues. Srsf3 KO in hepatocytes enhances DEN-induced liver cancer and disrupts the sex disparity in DEN-induced liver cancer. Comparing to Srsf3 WT liver cancer, Srsf3 KO significantly increases Sox4, E2f1, Trpv4, Trim6, and Myc expression, but does not so in Erbb2 breast cancer. Srsf3 KO inhibits expression of Mfsd4a and Eif4a2 in breast cancer but enhances Mfsd4a and Eif4a2 expression in liver cancer. Moreover, Srsf3 KO suppresses the expression of ERα and Foxa genes to reduce Lifr and Egfr but induce Myc expression and promote liver cancer in female mice. Together, our data highlight a new functional paradigm of SRSF3 at its physiological level in tissue context-dependent gene regulation.

  PublisherOA PDFDOI

• Stoking an anti-liver cancer immune response with cryoablation plus an intratumoral TLR9 agonist and dual checkpoint inhibitors

  Research Square · 2025-10-25

  preprintOpen access
  PublisherOA PDFDOI

• Single-cell transcriptomics reveals immune remodeling of the murine lung microenvironment following chronic house dust mite exposure

  Frontiers in Immunology · 2025-11-27 · 1 citations

  articleOpen access

  Introduction House dust mite (HDM) is a common environmental aeroallergen strongly associated with asthma and chronic airway inflammation. While HDM exposure is known to induce T helper 2 (Th2)-mediated eosinophilic inflammation, its chronic effects on interleukin-1β (IL-1β)-associated neutrophilic inflammation remain poorly understood. This study used single-cell RNA sequencing (scRNA-seq) to investigate how chronic HDM exposure remodels the murine lung immune microenvironment, with a focus on the role of IL-1β in shaping HDM-driven immune responses. Methods Wild-type and Il1b -deficient mice on a C57BL/6 background were subjected to chronic HDM exposure over a 5-week period, and scRNA-seq was performed to characterize changes in the lung immune landscape. To enhance resolution of specific cell populations and better define their functional states, we performed subclustering, followed by pathway enrichment and transcription factor activity analyses. To account for endotoxin-dependent variability in HDM extracts, scRNA-seq was conducted using a low-lipopolysaccharide (LPS) HDM extract, while validation studies (histopathology, RT-qPCR, ELISA, and immunofluorescence) were performed using a high-LPS HDM extract. Results Our analysis demonstrates that chronic HDM exposure promotes the recruitment and activation of diverse immune cell populations in the lungs, including neutrophils, M2-polarized macrophages, B-2 (follicular) B cells, and multiple subsets of regulatory and effector CD4⁺ T cells. These populations contribute differently to the development or resolution of chronic lung inflammation through IL-1β-dependent and -independent mechanisms. scRNA-seq indicated that IL-1β signaling is critical for sustaining neutrophil and Th17 responses, whereas Il1b deficiency promotes Th2-skewed polarization. Validation experiments revealed that these effects are influenced by the endotoxin content of HDM extracts, which can override genotype-dependent effects. Discussion These findings demonstrate that chronic HDM exposure profoundly remodels the lung immune microenvironment through IL-1β-dependent and -independent mechanisms. The effects are context-dependent and modulated by the endotoxin content of HDM extracts, highlighting the complex immunomodulatory effects of HDM in inducing chronic lung inflammation.

  PublisherDOI

• In Vivo Bioluminescence Imaging of Tumor Progression in the Lewis Lung Carcinoma Orthotopic Mouse Model: A Comparison Between the Tail Vein Injection and Intranasal Instillation Methods

  Current Protocols · 2024-12-01 · 4 citations

  articleOpen access

  Metastasis remains a leading cause of cancer-related mortality, yet its study has been constrained by the lack of reliable animal models that faithfully replicate this complex process. Syngeneic models for studying lung cancer metastasis are limited, with the Lewis lung carcinoma (LLC) model being the most commonly employed. The conventional LLC orthotopic model involves injecting LLC cells intravenously (i.v.) via the tail vein into syngeneic C57BL/6 mice. However, this model has significant drawbacks, such as tumor development in multiple anatomical sites, incomplete lung tumor penetrance, and challenges in monitoring lung tumor growth. This article highlights the advantages of using luciferase-expressing LLC cells combined with bioluminescence imaging (BLI) to quantify tumor progression in live animals. We demonstrate that both white- and black-furred C57BL/6 mice can be used for BLI. Finally, we propose that intranasal (i.n.) instillation of LLC cells offers a valuable alternative to the traditional i.v. tail vein injection method, particularly for its simplicity and improved reproducibility. Although the LLC i.n. model does not recapitulate the metastasis process via the blood vascular route, it is an effective model for studying tumor seeding within the lungs and is particularly useful for analyzing the impact of the lung microenvironment on tumor initiation and progression. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Lewis lung carcinoma intravenous injection method Support Protocol: In vivo bioluminescence imaging Basic Protocol 2: Lewis lung carcinoma intranasal instillation method.

  PublisherOA PDFDOI

• Dysregulation of RNA splicing in early non-alcoholic fatty liver disease through hepatocellular carcinoma

  Scientific Reports · 2024-01-30 · 14 citations

  articleOpen access1st authorCorresponding

  While changes in RNA splicing have been extensively studied in hepatocellular carcinoma (HCC), no studies have systematically investigated changes in RNA splicing during earlier liver disease. Mouse studies have shown that disruption of RNA splicing can trigger liver disease and we have shown that the splicing factor SRSF3 is decreased in the diseased human liver, so we profiled RNA splicing in liver samples from twenty-nine individuals with no-history of liver disease or varying degrees of non-alcoholic fatty liver disease (NAFLD). We compared our results with three publicly available transcriptome datasets that we re-analyzed for splicing events (SEs). We found many changes in SEs occurred during early liver disease, with fewer events occurring with the onset of inflammation and fibrosis. Many of these early SEs were enriched for SRSF3-dependent events and were associated with SRSF3 binding sites. Mapping the early and late changes to gene ontologies and pathways showed that the genes harboring these early SEs were involved in normal liver metabolism, whereas those harboring late SEs were involved in inflammation, fibrosis and proliferation. We compared the SEs with HCC data from the TCGA and observed that many of these early disease SEs are found in HCC samples and, furthermore, are correlated with disease survival. Changes in splicing factor expression are also observed, which may be associated with distinct subsets of the SEs. The maintenance of these SEs through the multi-year oncogenic process suggests that they may be causative. Understanding the role of these splice variants in metabolic liver disease progression may shed light on the triggers of liver disease progression and the pathogenesis of HCC.

  PublisherOA PDFDOI

Recent grants

• A novel pathway of Th17/Th2 induction: The role of cAMP signaling in DC

  NIH · $2.9M · 2019–2023

• Time-restricted feeding and breast cancer

  NIH · $3.0M · 2016–2027

• SRSF3 Loss and Hepatocellular Carcinoma

  NIH · 2016–2019

• BLR&D Research Career Scientist Award Application

  NIH · 2020–2027

• NIH Grant I01BX000130

  NIH · 2014

Frequent coauthors

• Consuelo Sauceda

  VA San Diego Healthcare System

  52 shared

• Manasi Das

  University of California, San Diego

  49 shared

• Michael C. Pirrung

  University of California, Riverside

  38 shared

• Jerrold M. Olefsky

  University of California, San Diego

  38 shared

• M Fernández

  Consejo Nacional de Investigaciones Científicas y Técnicas

  37 shared

• Deepak Kumar

  33 shared

• Geert van den Bogaart

  University of Groningen

  33 shared

• Ailin Tao

  Second Affiliated Hospital of Guangzhou Medical University

  29 shared

Labs

• Clinical Diabetes Research GroupPI

Awards & honors

• Wilson Scholarship in Natural Sciences (1978 - 1981)
• The Royal Society, London European Exchange Fellowship (1986…
• Western Society for Clinical Investigation Young Faculty Awa…
• Institute for the Study of Aging Innovative Research Award (…
• Department of Veterans Affairs Research Career Scientist Awa…