Biology subjects

DelGaudio, N. L.

Publications and source records attributed to DelGaudio, N. L..

4 recordsLinked to original sources

bioRxiv2025

Tumor Genotype Dictates Mitochondrial and Immune Vulnerabilities in Liver Cancer

Although oncogenic alterations influence tumor metabolism, how they impose distinct metabolic programs within a shared tissue context remains poorly defined. Here, we developed a rapid mitochondrial profiling platform to compare metabolites and proteins in genetic models of primary liver cancer (PLC). Analyses of six genetically distinct PLCs revealed that mitochondrial energy metabolism is largely dictated by oncogene identity. Kras-driven tumors required creatine metabolism to buffer energy demands during early tumorigenesis, whereas c-MYC-driven tumors relied on oxidative phosphorylation. Among c-MYC-driven PLCs, Pten-deficient tumors accumulated mitochondrial phosphoethanolamine, a precursor for phosphatidylethanolamine (PE) synthesis. Inhibition of PE synthesis selectively impaired the growth of Pten-deficient tumors and extended survival, in part through enhanced infiltration of CD8 T cells and sensitization to TNF-mediated cytotoxicity. Mechanistically, loss of PE elevated surface TNF receptor 2 (TNFR2), promoting TNF signaling and pro-inflammatory response. These findings uncover genotype-specific mitochondrial metabolic liabilities and establish PE synthesis as a tumor-intrinsic mechanism of immune evasion in PLC.

cancer biology↗

bioRxiv2024

A mouse model to study glutathione limitation in vivo

Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are linked to many diseases, including cancer and neurodegenerative disorders, determining the function of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from Streptococcus Thermophilus (GshF). GshF expression allows efficient production of GSH in the cytosol and mitochondria and prevents cell death in response to GSH depletion, but not ferroptosis, indicating that GSH is not a limiting factor under lipid peroxidation. CRISPR screens using engineered enzymes revealed metabolic liabilities under compartmentalized GSH depletion. Finally, GshF expression in mice is embryonically lethal but sustains postnatal viability when restricted to adulthood. Overall, our work identifies a conditional mouse model to investigate the role of GSH availability in physiology and disease.

genetics↗

bioRxiv2023

Suppression of epithelial proliferation and tumorigenesis by immunoglobulin A

Immunoglobulin A (IgA) is the most abundant antibody isotype produced across mammals and plays a specialized role in mucosal homeostasis1. Constantly secreted into the lumen of the intestine, IgA binds commensal microbiota to regulate their colonization and function2,3 with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex aetiology and comorbidities4-8. Using genetically and environmentally controlled mice, here we show that IgA-deficient animals have increased susceptibility to endogenous colorectal tumours. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to both reduce steady-state proliferation and protect mice from tumours, but this function was due to antibody structure rather than binding specificity. In both organoid and monolayer culture systems, IgA directly suppressed epithelial growth. Co-immunoprecipitation mass spectrometry and a targeted CRISPR screen identified DMBT1 as an IgA-binding epithelial surface protein required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 regulate Notch signalling and tune the normal cycling of absorptive colonocyte progenitors. In mice, deleting the transmembrane and cytoplasmic signalling portions of DMBT1 or blocking Notch signalling was sufficient to reverse both the increased proliferation and tumour susceptibility of IgA knockouts. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.

immunology↗

bioRxiv2020

Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition

Previous studies have established that the cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity. However, the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to cytotoxic chemotherapy and express high levels of the transcription factor Evi1 compared to leukemias derived from myeloid progenitors. Here, we compared drug sensitivity and expression profiles of murine and human leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for Evi1 in modulating p53 protein stability and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 inhibitors in addition to classical genotoxic stresses. p53 loss-of-function in Evi1low progenitor-derived leukemias induces resistance to LSD1 inhibition. By contrast, Evi1high leukemias are sensitized to LSD1 inhibition by the BH3 mimetic venetoclax, resulting in enhanced apoptosis and greater reductions in disease burden. Our findings demonstrate a cell-of-origin determined novel role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in high-risk, chemoresistant EVI1high AML.

cancer biology↗