Biology subjects

Barrow, J.

Publications and source records attributed to Barrow, J..

4 recordsLinked to original sources

bioRxiv2026

SIRT5 acts in the tumor microenvironment via endothelial cell metabolism to support breast cancer growth

Triple-negative breast cancer (TNBC) is characterized by aggressive progression and poor prognosis, partly due to abnormal angiogenesis. While the metabolic reprogramming of tumor cells is well characterized, the metabolic regulation of tumor-associated endothelial cells (ECs) remains unclear. Here, we identified the mitochondrial deacylase SIRT5, which has established tumor-promoting roles in TNBC cells, as a key regulator of endothelial metabolic homeostasis and tumor angiogenesis. SIRT5-deficient host mice showed significant defects in supporting the growth of orthotopic SIRT5-proficient mammary tumor transplants, and the resulting neoplasms showed defects in tumor vascularization. In a 3D microfluidic vessel-on-chip model, SIRT5 loss compromised vascular barrier integrity and EC sprouting. Mechanistically, SIRT5-deficient ECs exhibited diminished mitochondrial respiratory capacity but apparently normal glycolysis. SIRT5 loss also caused increased mitochondrial reactive oxygen species levels, and a mitochondrial antioxidant rescued the endothelial cell defects following SIRT5 loss, indicating that SIRT5-mediated mitochondrial redox homeostasis in the tumor microenvironment is necessary to maintain vascular function. Orthotopic co-transplantation of TNBC and EC cells with or without SIRT5 knockdown demonstrated that endothelial SIRT5 promotes increased tumor growth in vivo. These results suggest that targeting SIRT5 offers a potential therapeutic strategy to disrupt tumor angiogenesis and suppress TNBC progression by targeting the metabolic vulnerabilities of the tumor endothelium.

cancer biology↗

bioRxiv2024

Small molecule oxybutynin rescues proliferative capacity of complex III-defective MPCs

Mitochondrial disease encompasses a group of genetically inherited disorders hallmarked by an inability of the respiratory chain to produce sufficient ATP. These disorders present with multisystemic pathologies that predominantly impact highly energetic tissues such as skeletal muscle. There is no cure or effective treatment for mitochondrial disease. We have discovered a small molecule known as oxybutynin that can bypass Complex III mitochondrial dysfunction in primary murine and human skeletal muscle progenitor cells (MPCs). Oxybutynin administration improves MPC proliferative capacity, enhances cellular glycolytic function, and improves myotube formation. Mechanistically, results from our isothermal shift assay indicates that oxybutynin interacts with a suite of proteins involved in mRNA processing which then trigger the upregulation biological pathways to circumvent CIII mitochondrial dysfunction. Taken together, we provide evidence for the small molecule oxybutynin as a potential therapeutic candidate for the future treatment of CIII mitochondrial dysfunction.

cell biology↗

bioRxiv2023

DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma

Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long non-coding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo models of disease. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, an indicator of mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease. HighlightsFibrolamellar carcinoma (FLC) is a lethal liver cancer lacking effective therapeutic options. Ma et al. demonstrate that primate-specific RNA LINC00473 is enriched in tumor epithelial cells and functions to promote FLC growth and dysregulate cellular energetics, unveiling an important mechanism downstream of the fusion oncogene, DNAJB1-PRKACA, in FLC pathogenesis. In BriefO_LILINC00473 is consistently elevated in primary FLC tumor tissue from different patient cohorts and in multiple disease models. C_LIO_LIDP fusion, the signature oncoprotein of FLC, drives LINC00473 expression. C_LIO_LILINC00473 promotes FLC growth via anti-apoptotic function. C_LIO_LILINC00473 modulates FLC energetics by promoting glycolysis and altering mitochondrial fitness. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/543290v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@20e0f2org.highwire.dtl.DTLVardef@904fbborg.highwire.dtl.DTLVardef@62af84org.highwire.dtl.DTLVardef@f114be_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Decreased Colonic Activin Receptor Like Kinase 1 Disrupts Epithelial Barrier integrity and is associated with a poor clinical outcome in Crohns disease

ObjectiveIntestinal epithelial cell (IEC) barrier dysfunction is critical to the development of Crohns disease (CD). However, the mechanism is understudied. We recently reported increased microRNA-31-5p (miR-31-5p) expression in colonic IECs of CD patients, but downstream targets are unknown. DesignMiR-31-5p target genes were identified by integrative analysis of RNA- and small RNA-sequencing data from colonic mucosa and confirmed by qPCR in colonic IECs. Functional characterization of Activin Receptor-Like Kinase 1 (ACVRL1 or ALK1) in IECs was performed ex vivo using 2 dimensional-cultured human primary colonic IECs. The impact of altered colonic ALK1 signaling in CD for the risk of surgery and endoscopic relapse was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. ResultsALK1 was identified as a target of miR-31-5p in colonic IECs of CD patients and confirmed using a 3-UTR reporter assay. Activation of ALK1 restricted the proliferation of colonic IECs in an EdU proliferation assay and down-regulated the expression of stemness-related genes. Activated ALK1 signaling directed the fate of colonic IEC differentiation toward colonocytes. Down-regulated ALK1 signaling was associated with increased stemness and decreased colonocyte-specific marker expression in colonic IECs of CD patients compared to healthy controls. Activation of ALK1 enhanced epithelial barrier integrity in a trans-epithelial electrical resistance permeability assay. Lower colonic ALK1 expression was identified as an independent risk factor for surgery and associated with a higher risk of endoscopic relapse in CD patients. ConclusionDecreased colonic ALK1 disrupted colonic IEC barrier integrity and associated with deteriorated clinical outcomes in CD patients.

cell biology↗