Lessons Learned from Cancer Metabolism for Physiology and Disease.

Tumor cells divide rapidly and dramatically alter their metabolism to meet biosynthetic and bioenergetic needs. Through studying the aberrant metabolism of cancer cells, other contexts in which metabolism drives cell state transitions become apparent. In this work, we will discuss how principles established by the field of cancer metabolism have led to discoveries in the contexts of physiology and tissue injury, mammalian embryonic development, and virus infection. We present specific examples of findings from each of these fields that have been shaped by the study of cancer metabolism. We also discuss the next important scientific questions facing these subject areas collectively. Altogether, these examples demonstrate that the study of "cancer metabolism" is indeed the study of cell metabolism in the context of a tumor, and undoubtedly discoveries from each of the fields discussed here will continue to build on each other in the future.

Análise ética dos impactos da pandemia de COVID-19 na saúde de crianças e adolescentes / An ethical analysis of the impacts of the COVID-19 pandemic on the health of children and adolescents / Análisis ético acerca dos impactos de la pandemia COVID-19 en la salud de niños y adolescentes

A pandemia de COVID-19 trouxe impactos significativos para a vida de crianças e adolescentes em todo o mundo. Considerando esse contexto, o objetivo deste artigo foi examinar como as crianças e os adolescentes no Brasil foram impactados pela pandemia à luz de uma análise ética. Para tanto, uma análise interpretativa de estudos brasileiros sobre a saúde da criança e do adolescente durante a pandemia foi realizada. A tarefa de reconhecer essa dimensão ética é importante para entender como as respostas a situações de crise, tais como a presente situação da pandemia de COVID-19, podem ser moldadas e identificar quais as prioridades de ação de acordo com todas as partes interessadas, situando a criança entre essas partes de interesse. A análise demonstrou que tanto os efeitos diretos quanto os indiretos implicam em processos de tomada de decisão que precisam utilizar e sustentar o direito de participação da criança para que a ação tomada esteja o máximo possível focada nos melhores interesses da criança. Contudo, a realidade brasileira tem demonstrado uma exclusão estrutural das vozes infantis. Recomenda-se que mais estudos sejam conduzidos a fim de aprofundar o conhecimento sobre os melhores interesses das crianças e sua participação nas ações tomadas durante a pandemia

The COVID-19 pandemic has impacted the lives of children and adolescents around the world. This article aims to examine how the pandemic has impacted children and adolescents in Brazil using an ethical analysis. An interpretive analysis of Brazilian studies on child and adolescent health during the pandemic was conducted. The task of recognizing this ethical dimension is important to understand how responses to crisis situations, such as the current situation of the COVID-19 pandemic, can be shaped and where are the priorities for action according to all stakeholders, situating the child between these parts of interest. Our analysis highlighted both direct and indirect effects surrounding the decision-making processes for children in the COVID-19 pandemic reality. These decisional processes must sustain the child's right to participation to ascertain that the action taken is in the child's best interests. However, Brazilian reality has shown a structural exclusion of children's voices in decisions that affect them, particularly related to the effects of the pandemics in their lives. More studies must be conducted to deepen the knowledge about children's best interests and their participation in actions planning during the pandemic

La pandemia de COVID-19 ha afectado las vidas de niños y adolescentes de todo el mundo. Este artículo tiene como objetivo examinar cómo la pandemia ha afectado a los niños y adolescentes en Brasil mediante un análisis ético. Se realizó un análisis interpretativo de los estudios brasileños sobre salud del niño y del adolescente durante la pandemia. La tarea de reconocer esta dimensión ética es importante para entender cómo las respuestas a situaciones de crisis, como la situación actual de la pandemia COVID-19, pueden configurarse y dónde están las prioridades de acción según todos los actores, situando al niño entre estas partes. de interés. Estos procesos de decisión deben sustentar el derecho del niño a la participación para asegurarse de que las medidas tomadas respondan al interés superior del niño. Sin embargo, la realidad brasileña ha mostrado una exclusión estructural de las voces de los niños en las decisiones que los afectan, particularmente en relación con los efectos de las pandemias en sus vidas. Se deben realizar más estudios para profundizar el conocimiento sobre el interés superior de los niños y su participación en la planificación de acciones durante la pandemia

Glutamine deprivation triggers NAGK-dependent hexosamine salvage.

Tumors frequently exhibit aberrant glycosylation, which can impact cancer progression and therapeutic responses. The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. Prior studies have identified the HBP as a promising therapeutic target in pancreatic ductal adenocarcinoma (PDA). The HBP requires both glucose and glutamine for its initiation. The PDA tumor microenvironment is nutrient poor, however, prompting us to investigate how nutrient limitation impacts hexosamine synthesis. Here, we identify that glutamine limitation in PDA cells suppresses de novo hexosamine synthesis but results in increased free GlcNAc abundance. GlcNAc salvage via N-acetylglucosamine kinase (NAGK) is engaged to feed UDP-GlcNAc pools. NAGK expression is elevated in human PDA, and NAGK deletion from PDA cells impairs tumor growth in mice. Together, these data identify an important role for NAGK-dependent hexosamine salvage in supporting PDA tumor growth.

Inside tumors, cancer cells often have to compete with each other for food and other resources they need to survive. This is a key factor driving the growth and progression of cancer. One of the resources cells need is a molecule called UDP-GlcNAc, which they use to modify many proteins so they can work properly. Because cancer cells grow quickly, they likely need much more UDP-GlcNAc than healthy cells. Many tumors, including those derived from pancreatic cancers, have very poor blood supplies, so their cells cannot get the nutrients and other resources they need to grow from the bloodstream. This means that tumor cells have to find new ways to use what they already have. One example of this is developing alternative ways to obtain UDP-GlcNAc. Cells require a nutrient called glutamine to produce UDP-GlcNAc. Limiting the supply of glutamine to cells allows researchers to study how cells are producing UDP-GlcNAc in the lab. Campbell et al. used this approach to study how pancreatic cancer cells obtain UDP-GlcNAc when their access to glutamine is limited. They used a technique called isotope tracing, which allows researchers to track how a specific chemical is processed inside the cell, and what it turns into. The results showed that the pancreatic cancer cells do not make new UDP-GlcNAc but use a protein called NAGK to salvage GlcNAc (another precursor of UDP-GlcNAc), which may be obtained from cellular proteins. Cancer cells that lacked NAGK formed smaller tumors, suggesting that the cells grow more slowly because they cannot recycle UDP-GlcNAc fast enough. Pancreatic cancer is one of the most common causes of cancer deaths and is notable for being difficult to detect and treat. Campbell et al. have identified one of the changes that allows pancreatic cancers to survive and grow quickly. Next steps will include examining the role of NAGK in healthy cells and testing whether it could be targeted for cancer treatment.

Can Social Media Be Used as a Community-Building and Support Tool among Jewish Women Impacted by Breast and Ovarian Cancer? An Evidence-Based Observational Report.

About 1 in 40 Ashkenazi Jewish women carry a deleterious mutation in BRCA1/2 genes, predisposing them to hereditary breast/ovarian cancer (HBOC). Thus, efforts to prevent and control HBOC in the US must include sufficient outreach and education campaigns within and across the Jewish community. Social media (SM) is utilized in public health campaigns focused on cancer, but very little is known about the efficacy of those efforts when directed toward Jewish women at risk for ("previvors") and affected by ("survivors") HBOC. Here, we report on outcomes of a targeted SM campaign for this population, as led by a national not-for-profit HBOC advocacy organization. Mixed-methods data were obtained from n = 393 members of the community, including n = 20 key informants, and analyzed for engagement and satisfaction with its SM campaign and HBOC resources. Message recipients identified the SM campaign as helpful/meaningful (82%), of 'newsworthy' value (78%), and actionable/navigable (71%): interviews revealed that women were more likely to engage with SM if/when it featured stories relevant to their personal cancer experiences. SM is a valuable public health education tool to address the comprehensive cancer control and prevention needs of those previving and surviving with HBOC, including high-risk Jewish women.

Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis.

Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes.

FBXW7 Triggers Degradation of KMT2D to Favor Growth of Diffuse Large B-cell Lymphoma Cells.

Mature B-cell neoplasms are the fifth most common neoplasm. Due to significant heterogeneity at the clinical and genetic levels, current therapies for these cancers fail to provide long-term cures. The clinical success of proteasome inhibition for the treatment of multiple myeloma and B-cell lymphomas has made the ubiquitin pathway an important emerging therapeutic target. In this study, we assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. FBXW7 targeted the frequently inactivated tumor suppressor KMT2D for protein degradation, subsequently regulating gene expression signatures related to oxidative phosphorylation (OxPhos). Loss of FBXW7 inhibited diffuse large B-cell lymphoma cell growth and further sensitized cells to OxPhos inhibition. These data elucidate a novel mechanism of regulation of KMT2D levels by the ubiquitin pathway and uncover a role of FBXW7 in regulating oxidative phosphorylation in B-cell malignancies. SIGNIFICANCE: These findings characterize FBXW7 as a prosurvival factor in B-cell lymphoma via degradation of the chromatin modifier KMT2D.

ATP-citrate lyase multimerization is required for coenzyme-A substrate binding and catalysis.

ATP-citrate lyase (ACLY) is a major source of nucleocytosolic acetyl-CoA, a fundamental building block of carbon metabolism in eukaryotes. ACLY is aberrantly regulated in many cancers, cardiovascular disease, and metabolic disorders. However, the molecular mechanisms determining ACLY activity and function are unclear. To this end, we investigated the role of the uncharacterized ACLY C-terminal citrate synthase homology domain in the mechanism of acetyl-CoA formation. Using recombinant, purified ACLY and a suite of biochemical and biophysical approaches, including analytical ultracentrifugation, dynamic light scattering, and thermal stability assays, we demonstrated that the C terminus maintains ACLY tetramerization, a conserved and essential quaternary structure in vitro and likely also in vivo Furthermore, we show that the C terminus, only in the context of the full-length enzyme, is necessary for full ACLY binding to CoA. Together, we demonstrate that ACLY forms a homotetramer through the C terminus to facilitate CoA binding and acetyl-CoA production. Our findings highlight a novel and unique role of the C-terminal citrate synthase homology domain in ACLY function and catalysis, adding to the understanding of the molecular basis for acetyl-CoA synthesis by ACLY. This newly discovered means of ACLY regulation has implications for the development of novel ACLY modulators to target acetyl-CoA-dependent cellular processes for potential therapeutic use.

Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis.

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS-mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA-producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT-ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA-dependent processes exerts anticancer effects. SIGNIFICANCE: Pancreatic cancer is among the deadliest of human malignancies. We identify a key role for the metabolic enzyme ACLY, which produces acetyl-CoA, in pancreatic carcinogenesis. The data suggest that acetyl-CoA use for histone acetylation and in the mevalonate pathway facilitates cell plasticity and proliferation, suggesting potential to target these pathways.See related commentary by Halbrook et al., p. 326.This article is highlighted in the In This Issue feature, p. 305.

Metabolic Signaling to the Nucleus in Cancer.

Nutrient-sensing mechanisms ensure that cellular activities are coordinated with nutrient availability. Recent work has established links between metabolite pools and protein post-translational modifications, as metabolites are substrates of enzymes that add or remove modifications such as acetylation, methylation, and glycosylation. Cancer cells undergo metabolic reprogramming and exhibit metabolic plasticity that allows them to survive and proliferate within the tumor microenvironment. In this article we review the evidence that, in cancer cells, nutrient availability and oncogenic metabolic reprogramming impact the abundance of key metabolites that regulate signaling and epigenetics. We propose models to explain how these metabolites may control locus-specific chromatin modification and gene expression. Finally, we discuss emerging roles of metabolites in regulating malignant phenotypes and tumorigenesis via transcriptional control. An improved understanding of how metabolic alterations in cancer affect nuclear gene regulation could uncover new vulnerabilities to target therapeutically.

Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism.

The androgen receptor (AR) plays a central role in prostate tumor growth. Inappropriate reactivation of the AR after androgen deprivation therapy promotes development of incurable castration-resistant prostate cancer (CRPC). In this study, we provide evidence that metabolic features of prostate cancer cells can be exploited to sensitize CRPC cells to AR antagonism. We identify a feedback loop between ATP-citrate lyase (ACLY)-dependent fatty acid synthesis, AMPK, and the AR in prostate cancer cells that could contribute to therapeutic resistance by maintaining AR levels. When combined with an AR antagonist, ACLY inhibition in CRPC cells promotes energetic stress and AMPK activation, resulting in further suppression of AR levels and target gene expression, inhibition of proliferation, and apoptosis. Supplying exogenous fatty acids can restore energetic homeostasis; however, this rescue does not occur through increased ß-oxidation to support mitochondrial ATP production. Instead, concurrent inhibition of ACLY and AR may drive excess ATP consumption as cells attempt to cope with endoplasmic reticulum (ER) stress, which is prevented by fatty acid supplementation. Thus, fatty acid metabolism plays a key role in coordinating ER and energetic homeostasis in CRPC cells, thereby sustaining AR action and promoting proliferation. Consistent with a role for fatty acid metabolism in sustaining AR levels in prostate cancer in vivo, AR mRNA levels in human prostate tumors correlate positively with expression of ACLY and other fatty acid synthesis genes. The ACLY-AMPK-AR network can be exploited to sensitize CRPC cells to AR antagonism, suggesting novel therapeutic opportunities for prostate cancer.