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.
Pancreatic cancer: Advances and challenges Halbrook, Christopher J.; Lyssiotis, Costas A.; Pasca di Magliano, Marina ...
Cell,
04/2023, Letnik:
186, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic ...tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant disease.
Enabled by technological development on various fronts, our understanding of the complexity in the biology of pancreatic ductal adenocarcinoma deepens, laying the foundation for promising translation of the biological insights into clinically actionable advances.
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.
Ferroptosis is an iron-dependent, nonapoptotic form of regulated cell death triggered by impaired redox and antioxidant machinery and propagated by the accumulation of toxic lipid peroxides. A ...compendium of experimental studies suggests that ferroptosis is tumor-suppressive. Sensitivity or resistance to ferroptosis can be regulated by cell-autonomous and non-cell-autonomous metabolic mechanisms. This includes a role for ferroptosis that extends beyond the tumor cells themselves, mediated by components of the tumor microenvironment, including T cells and other immune cells. Herein, we review the intrinsic and extrinsic factors that promote the sensitivity of cancer cells to ferroptosis and conclude by describing approaches to harness the full utility of ferroptotic agents as therapeutic options for cancer therapy.
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.
Oncogenic mutations in KRAS drive common metabolic programmes that facilitate tumour survival, growth and immune evasion in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal ...adenocarcinoma. However, the impacts of mutant KRAS signalling on malignant cell programmes and tumour properties are also dictated by tumour suppressor losses and physiological features specific to the cell and tissue of origin. Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.
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.
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