Exploiting the bad eating habits of Ras-driven cancers

White, Eileen

doi:10.1101/gad.228122.113

Cited by 159 publications

(157 citation statements)

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“…Autophagy thereby functions to promote metabolic homeostasis and survival that is essential during nutrient deprivation. While it is generally appreciated that autophagy-mediated degradation of intracellular proteins and organelles provides metabolic substrates during starvation, the exact substrates that are important and the metabolic pathways they support remain to be identified (2,10). The metabolic role for autophagy partly overlaps with the protein and organelle quality control function and further broadens the impact autophagy has on mammalian physiology and disease.…”

Section: Autophagy Is a Tissue-specific Regulator Of Homeostasis And mentioning

confidence: 99%

The role for autophagy in cancer

White¹

2015

J. Clin. Invest.

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1,107

965

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Autophagy is a tissue-specific regulator of homeostasis and survivalAutophagy captures and degrades intracellular components such as proteins and organelles to sustain metabolism and homeostasis. Low levels of basal autophagy prevent the gradual accumulation of damaged proteins and organelles in tissues that is toxic over time; thus, autophagy plays an important role in protein and organelle quality control (1). Identification of the autophagy substrates that are deregulated in autophagy-deficient cells and tissues is important to understand the biological role and tissue specificity of autophagy. Determination of the global impact of autophagy on the cellular proteome would be a significant advance, as we are only beginning to understand the broad scope of autophagy substrates and the functional consequence of deregulating their degradation and recycling.Some tissues such as liver, brain, and muscle are particularly dependent on autophagy to prevent the buildup of damaged mitochondria and protein aggregates containing the autophagy substrate p62/SQSTM1 (p62) and ubiquitin (1). Accumulation of defective mitochondria that results from impaired autophagy can perturb metabolism and generate oxidative stress (2). Autophagy also mitigates ER stress, and autophagy defects can produce accumulation of chaperone proteins that increase the unfolded protein burden (3, 4). Select protein elimination by autophagy is also important for homeostasis. The toxicity of autophagy defects in liver is partly ameliorated by deficiency in the autophagy substrate p62, but this is not the case for the brain (5, 6). The recent revelation that autophagy is important for recycling iron complexed with ferritin through ferritinophagy may be critical for iron homeostasis in many tissues, potentially including brain (7).The accumulation of, or imbalance in, levels of some cellular components caused by autophagy defects may be indirect. For example, lipid accumulation in autophagy-deficient liver and some lung tumors can arise from defects in the autophagy of lipid droplets through lipophagy (8) or indirectly from defects in mitochondrial fatty acid oxidation (FAO) that repress lipid catabolism (9). These findings collectively demonstrate the broad effects of autophagy on cellular homeostasis at the level of substrate removal, maintenance of organelle function, and detoxification. Thus, autophagy dependence is tissue specific, not only for the general requirement for the level of autophagic activity, but also for the nature of the substrates that require autophagy-mediated elimination or recycling.Acute autophagy induction is critical for yeast and normal mammalian cells and mammals to survive starvation, which is attributed to the recycling of intracellular components into metabolic pathways (2). Autophagy thereby functions to promote metabolic homeostasis and survival that is essential during nutrient deprivation. While it is generally appreciated that autophagy-mediated degradation of intracellular proteins and organelles provides metabolic s...

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Section: Autophagy Is a Tissue-specific Regulator Of Homeostasis And mentioning

confidence: 99%

The role for autophagy in cancer

White¹

2015

J. Clin. Invest.

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1,107

965

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“…However, with sustained autophagy, primary cells can incur critical depletion of organelles and experience subsequent cell death. In keeping with these contrasting effects of autophagy, experimental studies reveal a dual function of autophagy in cancer (Kimmelman 2011;White 2013). In normal cells, autophagy serves as a barrier for tumorigenesis through its quality control function; reciprocally, inactivation of autophagy causes accumulation of damaged cellular components, which results in genotoxic levels of ROS and the promotion of early neoplastic changes (Galluzzi et al 2015).…”

Section: Salvage Pathways-a Hallmark Of Pdac Metabolismmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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“…Changes in metabolism represent some of the first differences described between cancer and normal tissues, dating to Otto Warburg's initial observations that cancer tissues increase glucose uptake and have a tendency to ferment glucose despite the presence of oxygen (11). More recent work has connected increased glucose metabolism to oncogene activation (12), setting the stage for numerous studies detailing the role of oncogenes and tumor suppressors in regulating cancer cell metabolism to promote the accumulation of biomass necessary for enhanced proliferation (13)(14)(15). Because drugs are lacking to specifically treat patients with tumors harboring many mutations in genes such KRAS and TP53, one hope is to identify other pathway dependencies in these cancers (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

Mayers

Heiden

2017

Cancer Research

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Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids (BCAA) to extract nitrogen for nonessential amino acid and nucleotide synthesis, whereas pancreatic cancer obtains amino acids from catabolism of extracellular protein. These differences in amino acid metabolism translate into distinct pathway dependencies, as genetic disruption of the enzymes responsible for utilization of BCAA nitrogen limits the growth of lung tumors, but not pancreatic tumors. These data argue that some cancer metabolic phenotypes are defined by cancer tissue-of-origin and environment and that these features constrain the influence of genetic mutations on metabolism. A better understanding of the factors defining tumor nutrient utilization could be exploited to help improve cancer therapy.

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Exploiting the bad eating habits of Ras-driven cancers

Cited by 159 publications

References 50 publications

The role for autophagy in cancer

The role for autophagy in cancer

Genetics and biology of pancreatic ductal adenocarcinoma

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

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