Biology subjects

Perry, R. J.

Publications and source records attributed to Perry, R. J..

6 recordsLinked to original sources

bioRxiv2023

FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma

Metabolic homeostasis is one of the most exquisitely tuned systems in mammalian physiology. Metabolic homeostasis requires multiple redundant systems to cooperate to maintain blood glucose concentrations in a narrow range, despite a multitude of physiological and pathophysiological pressures. Cancer is one of the canonical pathophysiological settings in which metabolism plays a key role. In this study, we utilized REnal Gluconeogenesis Analytical Leads (REGAL), a liquid chromatography-mass spectrometry/mass spectrometry-based stable isotope tracer method that we developed to show that in conditions of metabolic stress, the fasting hepatokine fibroblast growth factor-21 (FGF-21)1, 2 coordinates a liver-brain-kidney axis to promote renal gluconeogenesis. FGF-21 promotes renal gluconeogenesis by enhancing {beta}2 adrenergic receptor (Adrb2)-driven, adipose triglyceride lipase (ATGL)-mediated intrarenal lipolysis. Further, we show that this liver-brain-kidney axis promotes gluconeogenesis in the renal parenchyma in mice and humans with renal cell carcinoma (RCC). This increased gluconeogenesis is, in turn, associated with accelerated RCC progression. We identify Adrb2 blockade as a new class of therapy for RCC in mice, with confirmatory data in human patients. In summary, these data reveal a new metabolic function of FGF-21 in driving renal gluconeogenesis, and demonstrate that inhibition of renal gluconeogenesis by FGF-21 antagonism deserves attention as a new therapeutic approach to RCC.

physiology↗

bioRxiv2022

Differential metabolic adaptations define responses of winner and loser oncogenic mutant stem cells in skin epidermis in vivo

Skin epithelial stem cells detect and correct aberrancies induced by oncogenic mutations. Different oncogenes invoke different mechanisms of epithelial tolerance: while wild-type cells outcompete {beta}-catenin-Gain-of-Function ({beta}catGOF) mutant cells, HrasG12V mutant cells outcompete wild-type cells1,2. Here we ask how metabolic states change as wild-type stem cells interface with mutant cells, and how this ultimately drives different cell competition outcomes. By adapting our live-imaging platform to track endogenous redox ratio (NAD(P)H/FAD) with single cell resolution in the same mice over time, we show that wild-type epidermal stem cells maintain robust redox ratio despite their heterogeneous cell cycle states. We discover that both {beta}catGOF and HrasG12V models lead to a rapid drop in redox ratios. However, the "winner" cells in each model (wild-type in {beta}catGOF and mutant in HrasG12V), rapidly recover their redox ratios, irrespective of the mutation induced. Using mass spectrometry (13C-LC-MS/MS)3, we find that both mutants increase flux through the oxidative tricarboxylic acid cycle, but the "winner" HrasG12V cells and the "loser" {beta}catGOF cells modulate glycolytic flux differently. Hence, we reveal the metabolic adaptations that define the hallmarks of winners and losers during cell competition in vivo and uncover the nodes of regulation unique to each cell fate.

cancer biology↗

bioRxiv2022

Tissue-Specific and Interorgan Metabolic Reprogramming Maintains Tolerance to Sepsis

Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness1. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged for both identification of new metabolic targets, and a deeper understanding of the metabolic fate of glutamine at the systemic and tissue-specific manner2-4. In critically ill patients versus elective surgical controls, skeletal muscle transcriptional metabolic reprogramming is comprised of reduced expression of genes involved in mitochondrial metabolism, electron transport, and glutamate transport, with concomitant increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. To analyze putative interorgan communications during sepsis, we performed systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model, cecal ligation and puncture. In the setting of drastically elevated inflammatory cytokines, we observed >10% body weight loss, >50% reductions in oxygen consumption and carbon dioxide production, and near full suppression of voluntary activity for the 48 hours following sepsis as compared to sham-operated controls. We found increased correlations in the metabolome between liver, kidney, and spleen, with drastic loss of correlations between the heart and quadriceps metabolome and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for skeletal and cardiac muscle during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamines contribution to TCA anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamines contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming, rather than global mitochondrial dysfunction, as a mechanistic consequence of sepsis. Using a multi-omic approach, we demonstrate a model by which sepsis-induced proteolysis fuels the livers production of anaplerotic substrates and the antioxidant glutathione to sustain tolerance to sepsis.

physiology↗

bioRxiv2022

Gene Expression and Tracer-Based Metabolic Flux Analysis Reveals Tissue-Specific Metabolic Scaling in vitro, ex vivo, and in vivo

Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have almost exclusively been restricted to mathematical modeling of oxygen consumption. The possibility that other metabolic processes scale with body size has not been studied. To address this gap in knowledge, we employed a systems approach spanning from transcriptomics to in vitro and in vivo tracer-based flux. Gene expression in livers of five species spanning a 30,000-fold range in mass revealed differential expression of genes related to cytosolic and mitochondrial metabolic processes, in addition to detoxication of oxidative damage. This suggests that transcriptional scaling of damage control mechanisms accommodates increased oxidative metabolism in smaller species. To determine whether flux through key implicated metabolic pathways scaled, we applied stable isotope tracer methodology to study multiple cellular compartments, tissues, and species. Comparing mice and rats, we demonstrate that while scaling of metabolic fluxes is not observed in the cell-autonomous setting, it is present in liver slices and in vivo. Together, these data reveal that metabolic scaling extends beyond oxygen consumption to numerous other metabolic pathways, and is likely regulated at the level of gene expression and substrate supply.

physiology↗

bioRxiv2021

A Precision Medicine Approach to Metabolic Therapy for Breast Cancer in Mice

Increasing evidence highlights the possibility for approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic therapies, and have recently been highlighted as a novel therapeutic approach to breast cancer. To our knowledge, however, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach to combining metabolic therapy with standard of care therapy for this devastating disease. In this study we combine the SGLT2 inhibitor dapagliflozin with paclitaxel chemotherapy in both lean and obese mice. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival in an insulin-dependent manner in some but not all breast tumors. Our data find a genetic signature for breast tumors most likely to respond to dapagliflozin in combination with paclitaxel. Tumors driven by mutations upstream of canonical insulin signaling pathways are likely to respond to such treatment, whereas tumors driven by mutations downstream of canonical insulin signaling are not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that breast cancer patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach. A clinical trial is currently in preparation, with an application recently submitted for Yale Human Investigations Committee approval, to test this hypothesis in breast cancer patients. One Sentence SummaryWe identify a driver mutation signature by which glucose-wasting metabolic therapy (dapagliflozin) enhances the efficacy of chemotherapy in mice with breast cancer.

cancer biology↗

bioRxiv2021

Multimodal Analysis Reveals Differential Immuno-Metabolic Features in Lung Squamous Cell Carcinoma and Adenocarcinoma

BackgroundThe relationship between systemic metabolism, immune function, and lung cancer is complex and remains poorly defined. Seemingly paradoxically, overweight and obesity confer an improved response to immune checkpoint inhibition in non-small cell lung cancer (NSCLC); however, it is not known whether excess body weight or adiposity impacts the immunometabolic tumor microenvironment. MethodsUtilizing three complementary National Cancer Institute-funded open-source databases containing 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (PET-CT) images for tumor and tissue glucose uptake, adipose tissue and skeletal muscle mass, histology annotated with tumor infiltrating leukocytes, and tumor RNA sequencing, we performed a retrospective cross-sectional analysis to examine phenotypic, metabolic, and genomic intersections of adiposity and tumor immune-metabolism in patients with lung adenocarcinoma (LUAD) versus squamous cell carcinoma (LUSC). ResultsOur data reveal distinct immunometabolomic features of LUSC as compared to LUAD: visceral fat content was negatively correlated with both tumor glucose uptake and leukocyte infiltration. Subcutaneous and visceral adiposity conferred different effects on the tumor genetic landscapes in both tumor types. LUSC tumors showed greater gene expression pathways related to pyruvate, glucose, amino acid, and lipid metabolism, in addition to significantly greater 18F-FDG uptake compared with LUAD, suggesting deeper metabolic regulation within the LUSC tumor microenvironment. ConclusionsSeveral immunometabolomic characteristics of LUSC and LUAD differ, including tumor glucose uptake and the associated metabolic pathways in the tumor, as well as the impact of visceral adiposity on tumor metabolism. These data may highlight opportunities to advance mechanistically targeted precision medicine approaches by better understanding the interplay between metabolic, immunologic, and genomic factors in lung cancer treatment.

cancer biology↗