Summary The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.
Previous studies showed that i.p. administration of C75, a potent inhibitor of fatty acid synthase (FAS), blocked fasting-induced up-regulation of orexigenic neuropeptides and down-regulation of anorexigenic neuropeptides in the hypothalami of mice. As a result, food intake and body weight were drastically reduced. Here we provide evidence supporting the hypothesis that hypothalamic malonyl-CoA, a substrate of FAS, is an indicator of global energy status and mediates the feeding behavior of mice. We use a sensitive recycling assay to quantify malonyl-CoA to show that the hypothalamic malonyl-CoA level is low in fasted mice and rapidly (<2 h) increases (Ϸ5-fold) on refeeding. Intracerebroventricular C75 ͉ acetyl-CoA carboxylase ͉ fatty acid synthase ͉ neuropeptides ͉ obesity T he hypothalamus monitors global energy status in higher animals (1-4). Specific regions within the hypothalamus, notably the arcuate nucleus, respond to changes in energy status by altering the expression͞secretion of neuropeptides that affect energy intake and expenditure. Thus, when energy intake exceeds expenditure expression of the orexigenic neuropeptides, i.e., NPY and AgRP, decreases whereas the expression of anorexigenic neuropeptides, i.e., proopiomelanocortin (POMC) and CART, increases (1). Signals triggered by these changes are transmitted to higher brain centers through second-order neurons that affect behavior leading to decreased food intake. Conversely, when energy expenditure exceeds intake, the inverse response occurs. Despite considerable progress in identifying many of the neuropeptides and circuits involved (1-4), the signaling mechanisms by which energy status is initially monitored by neurons of the hypothalamus are incompletely understood.Recent evidence (5, 6) has implicated malonyl-CoA, an intermediate in fatty acid biosynthesis, as a possible mediator in the hypothalamic signaling pathway that monitors energy status. We and others have detected both acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (6, 7), enzymes that catalyze the formation and utilization of malonyl-CoA, respectively, in a subset of hypothalamic neurons. A potent inhibitor of FAS, i.e., C75 (8), that would be expected to increase cellular malonyl-CoA, suppresses food intake and appropriately alters expression of the hypothalamic neuropeptide mRNAs described above (9). Also consistent with the ''malonyl-CoA hypothesis'' is a recent report of Gilbert et al. (10), who found that carotid infusion of obese (Zucker) rats with glucose and insulin suppressed food intake and this effect was prevented by the ACC inhibitor, 5-(tetradecyloxy)-2-furoic acid (TOFA), administered intracerebroventricularly (i.c.v.). Although these indirect lines of evidence support the hypothesis that malonyl-CoA participates in monitoring energy status in the hypothalamus, direct proof is still lacking.Most previous studies (5-7, 9, 11) compared the effects of C75 administered by i.p. injection to mice that had been fasted to increase appetite when presented with food....
Central nervous system control of energy balance affects susceptibility to obesity and diabetes, but how fatty acids, malonyl-CoA, and other metabolites act at this site to alter metabolism is poorly understood. Pharmacological inhibition of fatty acid synthase (FAS), rate limiting for de novo lipogenesis, decreases appetite independently of leptin but also promotes weight loss through activities unrelated to FAS inhibition. Here we report that the conditional genetic inactivation of FAS in pancreatic β cells and hypothalamus produced lean, hypophagic mice with increased physical activity and impaired hypothalamic PPARα signaling. Administration of a PPARα agonist into the hypothalamus increased PPARα target genes and normalized food intake. Inactivation of β cell FAS enzyme activity had no effect on islet function in culture or in vivo. These results suggest a critical role for brain FAS in the regulation of not only feeding, but also physical activity, effects that appear to be mediated through the provision of ligands generated by FAS to PPARα. Thus, 2 diametrically opposed proteins, FAS (induced by feeding) and PPARα (induced by starvation), unexpectedly form an integrative sensory module in the central nervous system to orchestrate energy balance. IntroductionHigher organisms adapt to changes in energy needs by assimilating peripheral hormonal and nutritional cues and integrating them in the central nervous system (1, 2). Even subtle defects in this system have deleterious consequences since modest excess weight in humans is associated with increased mortality (3, 4). The most thermodynamically efficient strategy for weight loss is appetite suppression, a difficult goal given the diversity of factors regulating food intake, ranging from amines and peptides to metabolites and fatty acids (reviewed in ref. 5).Fatty acid metabolism affects feeding behavior. Malonyl-CoA, an intermediary substrate controlling fatty acid flux, and carnitine palmitoyltransferase-1 (CPT-1), which allows fatty acids access to mitochondria for β-oxidation, have been independently implicated in regulating appetite (6, 7). Pharmacological inhibition of fatty acid synthase (FAS), the multifunctional enzyme that utilizes malonyl-CoA for the first committed step in fatty acid biosynthesis (8), with the compound C75 produces anorexia and weight loss in mice in the setting of increased malonyl-CoA (9). However, recent studies indicate that these effects on malonyl-CoA alone may not be sufficient to induce anorexia, as C75 also has an impact on the sympathetic nervous system and metabolic mediators, including PPARα and PPARγ coactivator-1 α (PGC1α) (10, 11). In addition,
Metastasis is a complex multistep process that involves critical interactions between cancer cells and a variety of stromal components in the tumor microenvironment, which profoundly influence the different aspects of the metastatic cascade and organ tropism of disseminating cancer cells. Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Evidence has demonstrated that ovarian cancer possesses specific metastatic tropism for the adipose-rich omentum, which has a pivotal role in the creation of the metastatic tumor microenvironment in the intraperitoneal cavity. Considering the distinct biology of ovarian cancer metastasis, the elucidation of the cellular and molecular mechanisms underlying the reciprocal interplay between ovarian cancer cells and surrounding stromal cell types in the adipose-rich metastatic microenvironment will provide further insights into the development of novel therapeutic approaches for patients with advanced ovarian cancer. Herein, we review the biological mechanisms that regulate the highly orchestrated crosstalk between ovarian cancer cells and various cancer-associated stromal cells in the metastatic tumor microenvironment with regard to the omentum by illustrating how different stromal cells concertedly contribute to the development of ovarian cancer metastasis and metastatic tropism for the omentum.
A) Diagram shows the single-cell RNA sequencing (scRNA-seq) and analysis workflow. We collected and processed normal fallopian tube tissues from ten cancer patients. All cells (directly sorted or maintained then sorted) were processed by using the Smart-Seq2 protocol. After the initial filtering, there were 3,877 good-quality cells left for downstream analysis. We compared the cells from three conditions to select the optimal condition for scRNA-seq. Cells from cultured or cryopreserved conditions, as well as cells carrying copy number variations and non-epithelial cells, were filtered out, which left 2,132 fresh FTE cells. Next, we used differential expression-based clustering to identify secretory subtypes.
A unique hypothalamic mechanism appears to link fatty acid synthesis to the expression of the key neuropeptides that regulate feeding behavior. The steady-state level of malonyl-CoA, an intermediate in fatty acid synthetic pathway, is thought to have a regulatory role in this system (1). The cellular level of malonyl-CoA is determined by its rate of formation catalyzed by acetyl-CoA carboxylase (ACC), 3 relative to its rate of utilization and degradation catalyzed by fatty acid synthase (FAS) and malonyl-CoA decarboxylase (MCD), respectively. Administration of C75, a potent inhibitor of FAS (2), suppresses food intake causing profound weight loss in both obese and lean mice (3, 4). With obese mice this weight loss is due primarily to a reduction of body fat (5). These effects are independent of leptin, since C75 causes weight loss in both leptindeficient (ob/ob) or leptin receptor-deficient (db/db) mice (3). C75 appears to exert its anorectic effect by disrupting the signaling system that regulates expression of the hypothalamic neuropeptides that control feeding behavior. Thus, C75 blocks the fasting-induced up-regulation of orexigenic (AgRP and NPY) and down-regulation of anorexigenic (CART and POMC) neuropeptides in the hypothalamus (3, 6). These and other findings suggested (7) that the accumulation of malonyl-CoA, a substrate of FAS and MCD, may mediate the changes in the expression of these neuropeptides and, therefore, food intake. Consistent with this hypothesis the administration of C75 leads to an increase of hypothalamic malonyl-CoA (7).Recent studies suggest that the changes in hypothalamic malonyl-CoA may depend upon the activity of hypothalamic AMP kinase (8, 9). It has long been recognized that AMP kinase in peripheral tissues (e.g. liver, adipose, and muscle) acts as a "sensor" of cellular energy charge (10, 11). Only recently, however, has evidence been obtained for the involvement of AMP kinase sensing in the hypothalamus (8, 12, 13) where global energy status is monitored and energy intake regulated (1). Conditions under which AMP kinase would be expected to be active and ACC inactive, e.g. in the fasted state, hypothalamic malonylCoA is extremely low (7). Consistent with this finding, the anorexigenic hormone leptin lowers AMP kinase activity in the hypothalamus (13). Likewise, the anorexigenic FAS inhibitor, C75, appears to reduce hypothalamic AMP kinase activity (8). These findings suggest that lowering hypothalamic AMP kinase activity is required to elicit the anorexigenic effects of leptin or C75. Lowering hypothalamic AMP kinase activity might be expected to activate ACC and elevate hypothalamic malonyl-CoA. While a direct linkage of the AMP kinase signaling system to changes in malonyl-CoA in the hypothalamus is suspected, it has not been demonstrated.Moreover, the role of malonyl-CoA as a regulator of feeding behavior in studies with C75 remains controversial because the specificity of the FAS inhibitor has been questioned (14 -16) raising the possibility of indirect effects. In the pr...
Malonyl-CoA functions as a mediator in the hypothalamic sensing of energy balance and regulates the neural physiology that governs feeding behavior and energy expenditure. The central administration of C75, a potent inhibitor of the fatty acid synthase (FAS), increases malonyl-CoA concentration in the hypothalamus and suppresses food intake while activating fatty acid oxidation in skeletal muscle. Closely correlated with the increase in muscle fatty acid oxidation is the phosphorylation͞inactivation of acetyl-CoA carboxylase, which leads to reduced malonyl-CoA concentration. Lowering muscle malonyl-CoA, a potent inhibitor of carnitine͞ palmitoyl-CoA transferase 1 (CPT1), releases CPT1 from inhibitory constraint, facilitating the entry of fatty acids into mitochondria for  oxidation. Also correlated with these events are C75-induced increases in the expression of skeletal muscle peroxisome proliferator-activated receptor ␣ (PPAR␣), a transcriptional activator of fatty acid oxidizing enzymes, and uncoupling protein 3 (UCP3), a thermogenic mitochondrial uncoupling protein. Phentolamine, an ␣-adrenergic blocking agent, prevents the C75-induced increases of skeletal muscle UCP3 and whole body fatty acid oxidation and C75-induced decrease of skeletal muscle malonyl-CoA. Thus, the sympathetic nervous system is implicated in the transmission of the ''malonyl-CoA signal'' from brain to skeletal muscle. Consistent with the up-regulation of UCP3 and PPAR␣ is the concomitant increase in the expression of PGC1␣, transcriptional coactivator of the UCP3 and PPAR␣-activated genes. These findings clarify the mechanism by which the hypothalamic malonyl-CoA signal is communicated to metabolic systems in skeletal muscle that regulate fatty acid oxidation and energy expenditure.acetyl-CoA carboxylase ͉ malonyl-CoA ͉ obesity ͉ uncoupling protein 3 T he hypothalamus monitors peripheral neural and hormonal signals that reflect changes in the energy status of higher animals (1). These signals are transmitted to higher brain centers, where the information is integrated and appropriate adjustments are made to alter feeding behavior. Recent evidence suggests that, in addition to signals that affect food intake, signals are also transmitted from the CNS to peripheral tissues, e.g., liver and skeletal muscle, to alter metabolic pathways involved in energy storage and expenditure (2, 3).Previous investigations have shown that intracerebroventricular (i.c.v.) administration of C75, a potent inhibitor of fatty acid synthase (FAS) (4), rapidly (Ͻ2 h) increases hypothalamic malonyl-CoA concentration (5), suppresses expression of orexigenic neuropeptides (e.g., NPY and AgRP), and activates expression of anorexigenic neuropeptides (e.g., ␣MSH and CART) (6). These changes correlate closely with an abrupt curtailment of food intake and a loss of body weight (7). Compelling evidence indicates that changes in hypothalamic [malonyl-CoA], provoked by inhibition of FAS or by refeeding after fasting, serve as an intermediary in the signaling pathways that...
The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH can be accurately measured when informed by the molecular signatures of the normal cells of origin.We surveyed the transcriptomes of ~ 4000 normal fallopian tube epithelial (FTE) cells, the cells of origin of serous ovarian cancer (SOC), and identified six FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH that was previously unrecognized. Importantly, NGH-based stratification of ~1700 tumors robustly predicted survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC. Highlights 1. The projection of FTE subtypes refines the molecular classification of serous OC 2. Comprehensive single-cell profiling of FTE cells identifies 6 molecular subtypes 3. Substantial non-genetic heterogeneity of HGSOC identified in 1700 tumors 4. A mesenchymal-high HGSOC subtype is robustly correlated with poor prognosis
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