Diabetes commonly affects cancer patients. We investigated the influence of diabetes on breast cancer biology using a three-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.
Gatikrushna Panigrahi, Julián Candia, Tiffany H. Dorsey, Wei Tang, Yuuki Ohara, Jung S. Byun, Tsion Z. Minas, Amy L. Zhang, Anuoluwapo Ajao, Ashley Cellini, Harris G. Yfantis, Amy L. Flis, Dean Mann, Olga Ioffe, Xin Wei Wang, Huaitian Liu, Christopher A. Loffredo, Anna Maria Napoles, Stefan Ambs
Albuminuria and podocyte injury are the key cellular events in the progression of diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is a nucleocytosolic enzyme responsible for the regulation of metabolic homeostasis in mammalian cells. This study aimed to investigate the possible roles of ACSS2 in kidney injury in DN. We constructed an ACSS2-deleted mouse model to investigate the role of ACSS2 in podocyte dysfunction and kidney injury in diabetic mouse models. In vitro, podocytes were chosen and transfected with ACSS2 siRNA and ACSS2 inhibitor and treated with high glucose. We found that ACSS2 expression was significantly elevated in the podocytes of patients with DN and diabetic mice. ACSS2 upregulation promoted phenotype transformation and inflammatory cytokine expression while inhibiting podocytes’ autophagy. Conversely, ACSS2 inhibition improved autophagy and alleviated podocyte injury. Furthermore, ACSS2 epigenetically activated raptor expression by histone H3K9 acetylation, promoting activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Pharmacological inhibition or genetic depletion of ACSS2 in the streptozotocin-induced diabetic mouse model greatly ameliorated kidney injury and podocyte dysfunction. To conclude, ACSS2 activation promoted podocyte injury in DN by raptor/mTORC1-mediated autophagy inhibition.
Jian Lu, Xue Qi Li, Pei Pei Chen, Jia Xiu Zhang, Liang Liu, Gui Hua Wang, Xiao Qi Liu, Ting Ting Jiang, Meng Ying Wang, Wen Tao Liu, Xiong Zhong Ruan, Kun Ling Ma
Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here we studied human iPSC-derived hepatic organoids and identified a robust induction in DIO2 expression (the deiodinase that activates T4 to T3) that occurs in hepatoblasts. The surge in D2-T3 per-sists until the hepatoblasts differentiate into hepatocytes- or cholangiocytes-like cells, nei-ther of which express DIO2. Preventing the induction of the D2-T3 signaling modified the expression of key transcription factors, decreased the number of hepatocyte-like cells by 60%, and increased the number of cholangiocyte-like cells by 55% without affecting the growth or the size of the mature liver organoid. Physiological levels of T3 could not ful-ly restore the transition from hepatoblasts to mature cells. This indicates that the timed surge in D2-T3 signaling critically determines the fate of developing human hepatoblasts and the transcriptome of the maturing hepatocytes, with physiological and clinical implica-tions for how the liver handles energy substrates.
Jorge Hidalgo-Álvarez, Federico Salas-Lucia, Diana Vera Cruz, Tatiana L. Fonseca, Antonio C. Bianco
In youth with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on beta cell function and insulin sensitivity. Youths with obesity and 2-h glucose≥120mg/dL underwent a 3-h OGTT and an isoglycemic intravenous glucose infusion to quantify the incretin effect. After 2 years, 30/39 participants had a repeated OGTT and were stratified into three tertiles according to the baseline incretin effect. Thirty participants completed the baseline and follow-up tests. The high-incretin effect group demonstrated a longitudinal increase in beta cell function (DIMM) (p=0.034), with greater insulin sensitivity at follow-up (p=0.034) and stable insulin secretion (φtotal) (p=0.077). A lower incretin effect at baseline was associated with a higher 1-h and 2-h glucose at follow-up (r = -0.558, p=0.001 and r = -0.533, p=0.004). The high-incretin effect group displayed a greater increase of GLP-17-36 than the moderate- and low-incretin group at baseline (p=0.008 and p=0.029), while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin respect to the high-incretin group (p=0.049).
Alfonso Galderisi, Domenico Tricò, Jessica O. Lat, Stephanie L. Samuels, Ram Weiss, Michelle Van Name, Bridget Pierpont, Nicola Santoro, Sonia Caprio
Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle-specific expression of Growth Arrest and DNA Damage Inducible Alpha (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MEKK4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.
George R. Marcotte, Matthew J. Miller, Hawley E. Kunz, Zachary C. Ryan, Matthew D. Strub, Patrick M. Vanderboom, Carrie J. Heppelmann, Sarah Chau, Zachary D. Von Ruff, Sean P. Kilroe, Andrew T. McKeen, Jason M. Dierdorff, Jennifer I. Stern, Karl A. Nath, Chad E. Grueter, Vitor A. Lira, Andrew R. Judge, Blake B. Rasmussen, K. Sreekumaran Nair, Ian R. Lanza, Scott M. Ebert, Christopher M. Adams
Glycolysis is highly enhanced in Pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for PDAC patients, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides new insights into crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.
Fumimasa Kitamura, Takashi Semba, Noriko Yasuda-Yoshihara, Kosuke Yamada, Akiho Nishimura, Juntaro Yamasaki, Osamu Nagano, Tadahito Yasuda, Atsuko Yonemura, Yilin Tong, Huaitao Wang, Takahiko Akiyama, Kazuki Matsumura, Norio Uemura, Rumi Itoyama, Luke Bu, Lingfeng Fu, Xichen Hu, Feng Wei, Kosuke Mima, Katsunori Imai, Hiromitsu Hayashi, Yo-ichi Yamashita, Yuji Miyamoto, Hideo Baba, Takatsugu Ishimoto
Obesity promotes triple-negative breast cancer (TNBC), and effective interventions are urgently needed to break the obesity-TNBC link. Epidemiologic studies indicate that bariatric surgery reduces TNBC risk, while evidence is limited or conflicted for weight loss via low-fat diet (LFD) or calorie restriction (CR). Using a murine model of obesity-driven TNBC, we compared the antitumor effects of vertical sleeve gastrectomy (VSG) with LFD, chronic CR, and intermittent CR. Each intervention generated weight and fat loss and suppressed tumor growth relative to obese mice (greatest suppression with CR). VSG and CR regimens exerted both similar and unique effects, as assessed using multi-omic approaches, in reversing obesity-associated transcriptional, epigenetic, secretome, and microbiota changes and restoring antitumor immunity. Thus, in a murine model of TNBC, bariatric surgery and CR each reverse obesity-driven tumor growth via shared and distinct antitumor mechanisms, and CR is superior to VSG in reversing obesity’s procancer effects.
Kristina Camp, Michael F. Coleman, Tori McFarlane, Steven S. Doerstling, Subreen A. Khatib, Erika T. Rezeli, Alfor G. Lewis, Alexander J. Pfeil, Laura A. Smith, Laura W. Bowers, Farnaz Fouladi, Weida Gong, Elaine M. Glenny, Joel S. Parker, Ginger L. Milne, Ian M. Carroll, Anthony A. Fodor, Randy J. Seeley, Stephen D. Hursting
Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor–deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.
Toshiya Matsukawa, Takashi Yagi, Tohru Uchida, Mashito Sakai, Masaru Mitsushima, Takao Naganuma, Hiroyuki Yano, Yuka Inaba, Hiroshi Inoue, Keisuke Yanagida, Masaaki Uematsu, Kazuki Nakao, Harumi Nakao, Atsu Aiba, Yoji Nagashima, Tetsuya Kubota, Naoto Kubota, Yoshihiko Izumida, Naoya Yahagi, Hiroyuki Unoki-Kubota, Yasushi Kaburagi, Shun-ichiro Asahara, Yoshiaki Kido, Hideo Shindou, Michiko Itoh, Yoshihiro Ogawa, Shiro Minami, Yasuo Terauchi, Kazuyuki Tobe, Kohjiro Ueki, Masato Kasuga, Michihiro Matsumoto
Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNAAla and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNALeu, we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination. Pathogenic burden reduction was less pronounced in myeloid compared with lymphoid lineages, despite C5024T compromising macrophage OXPHOS capacity. Rapid dilution of the C5024T mutation in T and B cell cultures could be induced by antigen receptor–triggered proliferation and was accelerated by metabolic stress conditions. Furthermore, we found C5024T to dysregulate CD8+ T cell metabolic remodeling and IFN-γ production after activation. Together, our data illustrate that the generation of memory lymphocytes shapes the mtDNA landscape, wherein pathogenic variants dysregulate the immune response.
Jingdian Zhang, Camilla Koolmeister, Jinming Han, Roberta Filograna, Leo Hanke, Monika Àdori, Daniel J. Sheward, Sina Teifel, Shreekara Gopalakrishna, Qiuya Shao, Yong Liu, Keying Zhu, Robert A. Harris, Gerald McInerney, Ben Murrell, Mike Aoun, Liselotte Bäckdahl, Rikard Holmdahl, Marcin Pekalski, Anna Wedell, Martin Engvall, Anna Wredenberg, Gunilla B. Karlsson Hedestam, Xaquin Castro Dopico, Joanna Rorbach
Genetic and metabolic changes in tissue and blood are reported to occur several years before glioma diagnosis. As gliomas are currently detected late, a liquid biopsy for early detection could impact the quality of life and prognosis of patients. Here, we present a nested case-control study of 550 pre-diagnostic glioma cases and 550 healthy controls, from the Northern Sweden Health and Disease study (NSHDS) and the European Prospective Investigation into Cancer and Nutrition (EPIC) study. We identified 93 significantly altered metabolites related to glioma development up to eight years before diagnosis. Out of these metabolites, a panel of 20 selected metabolites showed strong disease correlation and consistent progression pattern towards diagnosis in both the NSHDS and EPIC cohorts, and separated favorably future cases from controls independently of biological sex. The blood metabolite panel also successfully separated both lower grade glioma and glioblastoma cases from controls, up to eight years before diagnosis in NSHDS (glioma AUC=0.85, P=3.1e-12; glioblastoma AUC=0.85, P=6.3e-8), and up to two years before diagnosis in EPIC (glioma AUC=0.81, P=0.005; glioblastoma AUC=0.89, P=0.04). Pathway enrichment analysis detected metabolites related to the TCA-cycle, Warburg effect, gluconeogenesis, cysteine-, pyruvate- and tyrosine metabolism as the most affected.
Sebastian Löding, Ulrika Andersson, Rudolf Kaaks, Matthias B. Schulze, Valeria Pala, Ilona Urbarova, Pilar Amiano, Sandra M. Colorado-Yohar, Marcela Guevara, Alicia K. Heath, Anastasia Chrysovalantou Chatziioannou, Mattias Johansson, Lars Nyberg, Henrik Antti, Benny Björkblom, Beatrice Melin
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