Tumors are dynamic pseudoorgans that contain numerous cell types interacting to create a unique physiology. Within this network, the malignant cells encounter many challenges and rewire their ...metabolic properties accordingly. Such changes can be experienced and executed autonomously or through interaction with other cells in the tumor. The focus of this review is on the remodeling of the tumor microenvironment that leads to pathophysiologic interactions that are influenced and shaped by metabolism. They include symbiotic nutrient sharing, nutrient competition, and the role of metabolites as signaling molecules. Examples of such processes abound in normal organismal physiology, and such heterocellular metabolic interactions are repurposed to support tumor metabolism and growth. The importance and ubiquity of these processes are just beginning to be realized, and insights into their role in tumor development and progression are being used to design new drug targets and cancer therapies.
The tumor microenvironment is characterized by deregulated metabolic properties.
Intrinsic features (e.g., genetic programs in cancer cells) and extrinsic characteristics (e.g., oxygen tension, nutrient availability, pH) contribute to the deregulated metabolic profile of a tumor.
Malignant cells adapt through symbiotic metabolic interactions with other tumor cells.
These processes in tumors are repurposed pathways of normal heterocellular metabolic crosstalk.
Nutrient competition in the tumor microenvironment impairs effective antitumor immunity.
Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to ...successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease.
Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease.
The phosphoinositide 3-kinase (PI3K) pathway regulates multiple steps in glucose metabolism and also cytoskeletal functions, such as cell movement and attachment. Here, we show that PI3K directly ...coordinates glycolysis with cytoskeletal dynamics in an AKT-independent manner. Growth factors or insulin stimulate the PI3K-dependent activation of Rac, leading to disruption of the actin cytoskeleton, release of filamentous actin-bound aldolase A, and an increase in aldolase activity. Consistently, PI3K inhibitors, but not AKT, SGK, or mTOR inhibitors, cause a significant decrease in glycolysis at the step catalyzed by aldolase, while activating PIK3CA mutations have the opposite effect. These results point toward a master regulatory function of PI3K that integrates an epithelial cell’s metabolism and its form, shape, and function, coordinating glycolysis with the energy-intensive dynamics of actin remodeling.
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•PI3K signaling positively regulates aldolase activity in epithelial cells•PI3K activation mobilizes aldolase from F-actin, increasing flux through glycolysis•PI3K-to-aldolase signaling occurs through Rac and not through AKT•PI3K coordinates cytoskeletal dynamics and glycolysis in vitro and in vivo
Phosphoinositide 3-kinase directly coordinates glycolysis by activating Rac, which remodels the actin cytoskeleton to free actin-bound aldolase.
Pyruvate kinase M2 (PKM2) is upregulated in multiple cancer types and contributes to the Warburg effect by unclear mechanisms. Here we demonstrate that EGFR-activated ERK2 binds directly to PKM2 ...Ile 429/Leu 431 through the ERK2 docking groove and phosphorylates PKM2 at Ser 37, but does not phosphorylate PKM1. Phosphorylated PKM2 Ser 37 recruits PIN1 for cis-trans isomerization of PKM2, which promotes PKM2 binding to importin α5 and translocating to the nucleus. Nuclear PKM2 acts as a coactivator of β-catenin to induce c-Myc expression, resulting in the upregulation of GLUT1, LDHA and, in a positive feedback loop, PTB-dependent PKM2 expression. Replacement of wild-type PKM2 with a nuclear translocation-deficient mutant (S37A) blocks the EGFR-promoted Warburg effect and brain tumour development in mice. In addition, levels of PKM2 Ser 37 phosphorylation correlate with EGFR and ERK1/2 activity in human glioblastoma specimens. Our findings highlight the importance of nuclear functions of PKM2 in the Warburg effect and tumorigenesis.
Acetate Fuels the Cancer Engine Lyssiotis, Costas A.; Cantley, Lewis C.
Cell,
12/2014, Letnik:
159, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Cancer cells have distinctive nutrient demands to fuel growth and proliferation, including the disproportionate use of glucose, glutamine, and fatty acids. Comerford et al. and Mashimo et al. now ...demonstrate that several types of cancer are avid consumers of acetate, which facilitates macromolecular biosynthesis and histone modification.
Cancer cells have specific nutrient demands to fuel growth and proliferation, including the disproportionate use of glucose, glutamine, and fatty acids. Comerford et al. and Mashimo et al. now demonstrate that several types of cancer are avid consumers of acetate, which facilitates macromolecular biosynthesis and histone modification.
Cancer cells often select for mutations that enhance signalling through pathways that promote anabolic metabolism. Although the PI(3)K/Akt signalling pathway, which is frequently dysregulated in ...breast cancer, is a well-established regulator of central glucose metabolism and aerobic glycolysis, its regulation of other metabolic processes required for tumour growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI(3)K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating NRF2 to upregulate the GSH biosynthetic genes. Increased NRF2 stability is dependent on the Akt-mediated accumulation of p21(Cip1/WAF1) and GSK-3β inhibition. Consistently, in human breast tumours, upregulation of NRF2 targets is associated with PI(3)K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI(3)K/Akt-driven resistance to oxidative stress, initiation of tumour spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine synergizes with cisplatin to selectively induce tumour regression in PI(3)K pathway mutant breast cancer cells, both in vitro and in vivo. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI(3)K pathway mutant breast cancers.
Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, a frontline ...chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate that macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Together, these findings provide insights into the role of macrophages in pancreatic cancer therapy and have potential to inform the design of future treatments. Additionally, we report that pyrimidine release is a general function of alternatively activated macrophage cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.
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•Macrophages polarized by pancreatic cancer cells release pyrimidine nucleosides•Pyrimidine release is a property of alternatively activated macrophage metabolism•Deoxycytidine from macrophages inhibits gemcitabine treatment of cancer cells•Targeting macrophages enhances gemcitabine treatment of pancreatic cancer
Macrophages are present in high abundance in pancreatic ductal adenocarcinoma. Halbrook et al. identify that alternatively activated macrophages release a spectrum of pyrimidine nucleosides that are consumed by pancreatic cancer cells. Among these, deoxycytidine can directly compete with gemcitabine, hindering its efficiency as a chemotherapy.
Oncogenic KRAS is the key driver of pancreatic ductal adenocarcinoma (PDAC). We previously described a role for KRAS in PDAC tumor maintenance through rewiring of cellular metabolism to support ...proliferation. Understanding the details of this metabolic reprogramming in human PDAC may provide novel therapeutic opportunities. Here we show that the dependence on oncogenic KRAS correlates with specific metabolic profiles that involve maintenance of nucleotide pools as key mediators of KRAS-dependence. KRAS promotes these effects by activating a MAPK-dependent signaling pathway leading to MYC upregulation and transcription of the non-oxidative pentose phosphate pathway (PPP) gene RPIA, which results in nucleotide biosynthesis. The use of MEK inhibitors recapitulates the KRAS-dependence pattern and the expected metabolic changes. Antagonizing the PPP or pyrimidine biosynthesis inhibits the growth of KRAS-resistant cells. Together, these data reveal differential metabolic rewiring between KRAS-resistant and sensitive cells, and demonstrate that targeting nucleotide metabolism can overcome resistance to KRAS/MEK inhibition.
Cancer cells rely on certain extracellular nutrients to sustain their metabolism and growth. Solute carrier (SLC) transporters enable cells to acquire extracellular nutrients or shuttle intracellular ...nutrients across organelles. However, the function of many SLC transporters in cancer is unknown. Determining the key SLC transporters promoting cancer growth could reveal important therapeutic opportunities. Here we summarize recent findings and knowledge gaps on SLC transporters in cancer. We highlight existing inhibitors for studying these transporters, clinical trials on treating cancer by blocking transporters, and compensatory transporters used by cancer cells to evade treatment. We propose targeting transporters simultaneously or in combination with targeted therapy or immunotherapy as alternative strategies for effective cancer therapy.
In the past decade, there has been a resurgence of interest in elucidating how metabolism is altered in cancer cells and how such dependencies can be targeted for therapeutic gain. At the core of ...this research is the concept that metabolic pathways are reprogrammed in cancer cells to divert nutrients toward anabolic processes to facilitate enhanced growth and proliferation. Importantly, physiological cellular signaling mechanisms normally tightly regulate the ability of cells to gain access to and utilize nutrients, posing a fundamental barrier to transformation. This barrier is often overcome by aberrations in cellular signaling that drive tumor pathogenesis by enabling cancer cells to make critical cellular decisions in a cell-autonomous manner. One of the most frequently altered pathways in human cancer is the PI3K-Akt-mTOR signaling pathway. Here, we describe mechanisms by which this signaling network is responsible for controlling cellular metabolism. Through both the post-translational regulation and the induction of transcriptional programs, the PI3K-Akt-mTOR pathway coordinates the uptake and utilization of multiple nutrients, including glucose, glutamine, nucleotides, and lipids, in a manner best suited for supporting the enhanced growth and proliferation of cancer cells. These regulatory mechanisms illustrate how metabolic changes in cancer are closely intertwined with oncogenic signaling pathways that drive tumor initiation and progression.
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