BACKGROUND. Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI. METHODS. We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status. RESULTS. 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals. CONCLUSION. Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype. FUNDING. NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).
Nicolás Gómez-Banoy, Eduardo J. Ortiz, Caroline S. Jiang, Christian Dagher, Carlo Sevilla, Jeffrey Girshman, Andrew M. Pagano, Andrew J. Plodkowski, William A. Zammarrelli, Jennifer J. Mueller, Carol Aghajanian, Britta Weigelt, Vicky Makker, Paul Cohen, Juan C. Osorio
Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α–targeted therapies and deplete pathogenically stabilized HIF-2α.
Zachary A. Bacigalupa, Emily N. Arner, Logan M. Vlach, Melissa M. Wolf, Whitney A. Brown, Evan S. Krystofiak, Xiang Ye, Rachel A. Hongo, Madelyn Landis, Edith K. Amason, Kathryn E. Beckermann, W. Kimryn Rathmell, Jeffrey C. Rathmell
Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.
Nunziata Maio, Rotem Orbach, Irina T. Zaharieva, Ana Töpf, Sandra Donkervoort, Pinki Munot, Juliane Mueller, Tracey Willis, Sumit Verma, Stojan Peric, Deepa Krishnakumar, Sniya Sudhakar, A. Reghan Foley, Sarah Silverstein, Ganka Douglas, Lynn Pais, Stephanie DiTroia, Christopher Grunseich, Ying Hu, Caroline Sewry, Anna Sarkozy, Volker Straub, Francesco Muntoni, Tracey A. Rouault, Carsten G. Bönnemann
While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects β-cells and contributes to diabetes. However, the regulation of islet inflammation for maintaining glucose homeostasis remains largely unknown. Here, we identified pericytes as pivotal regulators of islet immune and β-cell function in health. Islets and pancreatic pericytes express various cytokines in healthy humans and mice. To interfere with the pericytic inflammatory response, we selectively inhibited the TLR/MyD88 pathway in these cells in transgenic mice. The loss of MyD88 impaired pericytic cytokine production. Furthermore, MyD88-deficient mice exhibited skewed islet inflammation with fewer cells, an impaired macrophage phenotype, and reduced IL-1β production. This aberrant pericyte-orchestrated islet inflammation was associated with β-cell dedifferentiation and impaired glucose response. Additionally, we found that Cxcl1, a pericytic MyD88-dependent cytokine, promoted immune IL-1β production. Treatments with either Cxcl1 or IL-1β restored the mature β-cell phenotype and glucose response in transgenic mice, suggesting a potential mechanism through which pericytes and immune cells regulate glucose homeostasis. Our study revealed pericyte-orchestrated islet inflammation as a crucial element in glucose regulation, implicating this process as a potential therapeutic target for diabetes.
Anat Schonblum, Dunia Ali Naser, Shai Ovadia, Mohammed Egbaria, Shani Puyesky, Alona Epshtein, Tomer Wald, Sophia Mercado-Medrez, Ruth Ashery-Padan, Limor Landsman
Leigh syndrome is the most common inherited mitochondrial disease in children and is often fatal within the first few years of life. In 2020, mutations in the gene encoding sulfide:quinone oxidoreductase (SQOR), a mitochondrial protein, were identified as a cause of Leigh syndrome. Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome. SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogens sulfide (H2S) levels. Because H2S is produced by both gut microbiota and host tissue, we tested whether metronidazole (a broad-spectrum antibiotic) or a sulfur-restricted diet rescues SqorΔN/ΔN mice from developing Leigh syndrome. Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice. Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome. Taken together, these observations suggest that mitochondrial SQOR is essential to prevent systemic accumulation of H2S. Administration of metronidazole or a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR.
Eiki Kanemaru, Kakeru Shimoda, Eizo Marutani, Masanobu Morita, Maria Miranda, Yusuke Miyazaki, Claire Sinow, Rohit Sharma, Fangcong Dong, Donald B. Bloch, Takaaki Akaike, Fumito Ichinose
BACKGROUND Preclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) — suggestive of cellular cholesterol accumulation — were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODS Monocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTS During a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes — ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) — and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSION These data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDING The MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.
Jingzhong Ding, Anh Tram Nguyen, Kurt Lohman, Michael T. Hensley, Daniel Parker, Li Hou, Jackson Taylor, Deepak Voora, Janet K. Sawyer, Elena Boudyguina, Michael P. Bancks, Alain Bertoni, James S. Pankow, Jerome I. Rotter, Mark O. Goodarzi, Russell P. Tracy, David M. Murdoch, Stephen S. Rich, Bruce M. Psaty, David Siscovick, Christopher Newgard, David Herrington, Ina Hoeschele, Steven Shea, James H. Stein, Manesh Patel, Wendy Post, David Jacobs Jr., John S. Parks, Yongmei Liu
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that exhibits diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects are uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disrupted lung uptake of fatty acids yet enhanced uptake of arachidonic acid, a precursor of pro-inflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multi-organ metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue.
Hosung Bae, Bo Ram Kim, Sunhee Jung, Johnny Le, Dana M. van der Heide, Wenjie Yu, Sang Hee Park, Brieanna M. Hilkin, Nicholas D. Gansemer, Linda S. Powers, Taekyung Kang, David K. Meyerholz, Victor L. Schuster, Cholsoon Jang, Michael J. Welsh
Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule L-2-hdroxyglutarate (L-2HG) is elevated in the most common histology of renal cancer. Similar to other oncometabolites, L-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that L-2HG remodels amino acid metabolism in renal cancer cells through the combined effects on histone methylation and RNA N6-methyladenosine (m6A). The combined effects of L-2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high L-2HG kidney cancers demonstrates reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high L-2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors.
Anirban Kundu, Garrett J. Brinkley, Hyeyoung Nam, Suman Karki, Richard Kirkman, Madhuparna Pandit, EunHee Shim, Hayley Widden, Juan Liu, Yasaman Heidarian, Nader H. Mahmoudzadeh, Alexander J. Fitt, Devin Absher, Han-Fei Ding, David K. Crossman, William J. Placzek, Jason W. Locasale, Dinesh Rakheja, Jonathan E. McConathy, Rekha Ramachandran, Sejong Bae, Jason M. Tennessen, Sunil Sudarshan
Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske Iron-Sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, they underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA-seq revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in alpha-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.
Gregory B. Waypa, Kimberly A. Smith, Paul T. Mungai, Vincent J. Dudley, Kathryn A. Helmin, Benjamin D. Singer, Clara Bien Peek, Joseph Bass, Lauren Beussink-Nelson, Sanjiv J. Shah, Gaston Ofman, J. Andrew Wasserstrom, William A. Muller, Alexander V. Misharin, G.R. Scott Budinger, Hiam Abdala-Valencia, Navdeep S. Chandel, Danijela Dokic, Elizabeth T. Bartom, Shuang Zhang, Yuki Tatekoshi, Amir Mahmoodzadeh, Hossein Ardehali, Edward B. Thorp, Paul T. Schumacker
Spinal Muscular Atrophy (SMA) is typically characterized as a motor neuron disease, but extra-neuronal phenotypes are present in almost every organ in severely affected patients and animal models. Extra-neuronal phenotypes were previously underappreciated as patients with severe SMA phenotypes usually died in infancy; however, with current treatments for motor neurons increasing patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to new treatment-modified phenotypes. Fatty liver is seen in SMA animal models , but generalizability to patients and whether this is due to hepatocyte-intrinsic Survival Motor Neuron (SMN) protein deficiency and/or subsequent to skeletal muscle denervation is unknown. If liver pathology in SMA is SMN-dependent and hepatocyte-intrinsic, this suggests SMN repleting therapies must target extra-neuronal tissues and motor neurons for optimal patient outcome. Here we showed that fatty liver is present in SMA and that SMA patient-specific iHeps were susceptible to steatosis. Using proteomics, functional studies and CRISPR/Cas9 gene editing, we confirmed that fatty liver in SMA is a primary SMN-dependent hepatocyte-intrinsic liver defect associated with mitochondrial and other hepatic metabolism implications. These pathologies require monitoring and indicate need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.
Damien Meng-Kiat Leow, Yang Kai Ng, Loo Chien Wang, Hiromi W.L. Koh, Tianyun Zhao, Zi Jian Khong, Tommaso Tabaglio, Gunaseelan Narayanan, Richard M. Giadone, Radoslaw M. Sobota, Shi-Yan Ng, Adrian K.K. Teo, Simon H Parson, Lee L. Rubin, Wei-Yi Ong, Basil T. Darras, Crystal J.J. Yeo