Biology subjects

Lesner, N. P.

Publications and source records attributed to Lesner, N. P..

5 recordsLinked to original sources

bioRxiv2026

Mitophagy Inhibition Promotes Survival and Mitochondrial Function in MYC-driven HCC

Hepatocellular carcinomas (HCC) are genetically heterogeneous cancers frequently characterized by MYC gene amplification or hyperactivating {beta}-catenin (CTNNB1) mutations. Analysis of TCGA transcriptomics revealed that MYC-driven HCC tumors have decreased expression of mtDNA-encoded genes, but increased expression of nuclear-encoded mitochondrial genes. To investigate this apparent discrepancy, we generated MYC- and CTNNB1-driven murine HCCs, all of which displayed aberrant mitochondrial metabolism. Notably, MYC-driven tumors exhibited significant reductions in OXPHOS and TCA cycle activity that correlated with increased ROS levels, as well as elevated mitochondrial turnover through mitochondrial fission and mitophagy. MYC induces the expression of nuclear respiratory factor 1 (NRF1), which regulates DRP1 and other genes to promote receptor-mediated mitophagy. Knocking out DRP1 reduced mitophagy and ROS levels and promoted survival of HCC-bearing mice. These results identify elevated mitochondrial turnover as a potential therapeutic target in MYC-driven HCC. SignificanceHepatocellular carcinoma can arise from multiple oncogenes, making targeted therapy more difficult. Here we show that tumors with MYC amplification lose mitochondrial function via fission and mitophagy upregulation. Targeting mitochondrial quality control results in increased survival suggesting a therapeutic window in MYC-driven HCC.

cancer biology↗

bioRxiv2026

Argininosuccinate Synthase 1 links hepatic urea cycle to whole body lipid metabolism

The hepatic urea cycle is consistently suppressed in liver disease and hepatocellular carcinoma (HCC), but whether loss of individual enzymes contributes to disease initiation and progression remains unknown. Using mice with hepatocyte-specific deletion of argininosuccinate synthase 1 (ASS1), the urea cycle enzyme that condenses citrulline and aspartate into argininosuccinate, we investigated the role of ASS1 in diet and carcinogen-induced liver disease progression. We found that complete loss of hepatic Ass1 is lethal, but high fat diet extends lifespan. Unexpectedly, animals with approximately 85% loss of hepatic Ass1 are completed protected from diet-induced obesity, liver steatosis, fibrosis, and HCC. We determined that hepatic Ass1 loss activates fatty acid oxidation in peripheral oxidative tissues leading to increased energy expenditure and protection from disease phenotypes. Moreover, targeting Ass1 after obesity onset promotes weight loss and reverses liver steatosis. These findings implicate hepatic ASS1 as a novel regulator of whole-body lipid metabolism that can be targeted to prevent obesity, liver disease, and HCC.

cancer biology↗

bioRxiv2024

Glutamine availability regulates cDC subsets in tissue

AbstractProliferating tumor cells take up glutamine for anabolic processes engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDC) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets - cDC1 and cDC2, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on Glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mTOR signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses. One Sentence SummaryType 1 conventional dendritic cells require glutamine to maintain their number in non-lymphoid tissue. SignificanceImmune evasion is a key hallmark of cancer; however, the underlying pathways are diverse, tumor-specific and not fully elucidated. Many tumor cells avidly import glutamine to support their anabolic needs, creating a glutamine-deficient tumor microenvironment (TME). Herein, using mouse models of soft tissue sarcomas, we show that glutamine depletion in TME leads to reduced type 1 conventional dendritic cells - a cell type that is critical for adaptive immune responses. This work is a paradigm for how tumor cell metabolism can regulate anti-tumor immune responses and will be foundational to future efforts targeting glutamine metabolism for cancer immunotherapy.

immunology↗

bioRxiv2023

Mitochondrial metabolism in primary and metastatic human kidney cancers

Most kidney cancers display evidence of metabolic dysfunction1-4 but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse 13C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U-13C]glucose varies across cancer subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours. Compared to the adjacent kidney, clear cell renal cell carcinomas (ccRCC) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is tissue intrinsic. Infusions of [1,2-13C]acetate and [U-13C]glutamine in patients, coupled with respiratory flux of mitochondria isolated from kidney and tumour tissue, reveal primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly have enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. In mice, stimulating respiration in ccRCC cells is sufficient to promote metastatic colonization. Altogether, these findings indicate that metabolic properties evolve during human kidney cancer progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin.

cancer biology↗

bioRxiv2021

Differential requirements for mitochondrial electron transport chain components in the adult murine liver

Mitochondrial electron transport chain (ETC) dysfunction due to mutations in the nuclear or mitochondrial genome is a common cause of metabolic disease in humans, and displays striking tissue specificity depending on the affected gene. The mechanisms underlying tissue specific phenotypes are not understood. Complex I (cI) is classically considered the entry point for electrons into the ETC, and in vitro experiments indicate that cI is required for basal respiration and maintenance of the NAD+/NADH ratio, an indicator of cellular redox status. This finding has largely not been tested in vivo. Here, we report that mitochondrial complex I (cI) is dispensable for homeostasis of the adult mouse liver; animals with hepatocyte-specific loss of cI function display no overt phenotypes or signs of liver damage, and maintain liver function, redox and oxygen status. Further analysis of cI-deficient livers did not reveal significant proteomic or metabolic changes, indicating little to no compensation is required in the setting of complex I loss. In contrast, complex IV (cIV) dysfunction in adult hepatocytes results in decreased liver function, impaired oxygen handling, steatosis, and liver damage, accompanied by significant metabolomic and proteomic perturbations. Metabolomic analysis suggests that the electron transfer flavoprotein complex constitutes a major route for electron entry into the hepatic ETC. Our results support a model whereby complex I loss is tolerated in the mouse liver because hepatocytes use alternative electron donors to fuel the mitochondrial ETC.

cell biology↗