Metastases arising from tumors have the proclivity to colonize specific organs, suggesting that they must rewire their biology to meet the demands of the organ colonized, thus altering their primary ...properties. Each metastatic site presents distinct metabolic challenges to a colonizing cancer cell, ranging from fuel and oxygen availability to oxidative stress. Here, we discuss the organ-specific metabolic adaptations that cancer cells must undergo, which provide the ability to overcome the unique barriers to colonization in foreign tissues and establish the metastatic tissue tropism phenotype.
Metabolic adaptations and the signaling events that control them promote the survival of pancreatic ductal adenocarcinoma (PDAC) at the fibrotic tumor site, overcoming stresses associated with ...nutrient and oxygen deprivation. Recently, rewiring of NADPH production has been shown to play a key role in this process. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells. However, de novo NADP+ is synthesized only through one known enzymatic reaction, catalyzed by NAD+ kinase (NADK). In this study, we show that oncogenic KRAS promotes protein kinase C (PKC)-mediated NADK phosphorylation, leading to its hyperactivation, thus sustaining both NADP+ and NADPH levels in PDAC cells. Together, our data show that increased NADK activity is an important adaptation driven by oncogenic signaling. Our findings indicate that NADK could serve as a much-needed therapeutic target for PDAC.
Metabolic reprogramming and metabolic plasticity allow cancer cells to fine-tune their metabolism and adapt to the ever-changing environments of the metastatic cascade, for which lipid metabolism and ...oxidative stress are of particular importance. NADPH is a central co-factor for both lipid and redox homeostasis, suggesting that cancer cells may require larger pools of NADPH to efficiently metastasize. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells; however, de novo NADP+ is synthesized only through one known enzymatic reaction, catalyzed by NAD+ kinase (NADK). Here, we show that NADK is upregulated in metastatic breast cancer cells enabling de novo production of NADP(H) and the expansion of the NADP(H) pools thereby increasing the ability of these cells to adapt to the challenges of the metastatic cascade and efficiently metastasize. Mechanistically, we found that metastatic signals lead to a histone H3.3 variant-mediated epigenetic regulation of the NADK promoter, resulting in increased NADK levels in cells with metastatic ability. Together, our work presents a previously uncharacterized role for NADK and de novo NADP(H) production as a contributor to breast cancer progression and suggests that NADK constitutes an important and much needed therapeutic target for metastatic breast cancers.
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•Breast cancer metastasis requires expansion of the NADP(H) pools to sustain the need for reductive power.•NADK is upregulated in breast cancer metastases to expand the NADP(H) pools.•NADK is regulated via dynamic incorporation of H3 variants during tumor progression.
Brain tumors are notoriously difficult to treat. Three recent Cancer Cell articles aim to uncover novel druggable targets in IDH mutant gliomas, diffuse midline gliomas, and medulloblastomas, ...respectively, and show that these brain tumor types shift their metabolism to become reliant on de novo pyrimidine synthesis.
Brain tumors are notoriously difficult to treat. Three recent Cancer Cell articles aim to uncover novel druggable targets in IDH mutant gliomas, diffuse midline gliomas, and medulloblastomas, respectively, and show that these brain tumor types shift their metabolism to become reliant on de novo pyrimidine synthesis.
The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards
. Nonetheless, our understanding of the complex relationship between age and cancer is ...still in its infancy
. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing
. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.
The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a major nutrient sensor and regulator of cellular metabolic flux. Reporting recently in Nature, Zabala-Letona et al. (2017) show ...that mTORC1 regulates an additional branch of metabolism in the cell—polyamine synthesis—that is important for prostate cancer tumorigenicity.
The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a major nutrient sensor and regulator of cellular metabolic flux. Reporting recently in Nature, Zabala-Letona et al. (2017) show that mTORC1 regulates an additional branch of metabolism in the cell—polyamine synthesis—that is important for prostate cancer tumorigenicity.
Metabolic adaptations, and the signaling events that control them, have been implicated in contributing to the capability of pancreatic ductal adenocarcinoma (PDAC) and triple negative breast cancer ...(TNBC) to adapt and survive stresses associated with nutrient and oxygen deprivation during the formation of the primary tumor, the progression into metastatic disease and the acquisition of drug resistance. The NADPH/NADP+ ratio plays a key role in maintaining tumor cell survival under such conditions of oxidative stress. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells. However, de novo NADP+ is only synthesized by one known enzymatic reaction catalyzed by NAD+ kinase (NADK), suggesting that high de novo synthesis of NADP+ by NADK may constitute a vital mechanism of survival utilized by cancer cells at various stages of tumorigenic process. My graduate studies show that oncogenic KRAS promotes PKC-mediated NADK phosphorylation and consequently leads to its hyperactivation, a phenomenon that is important for sustaining NADPH levels and redox balance in PDAC cells. My work indicates that increased NADK activity is a critical adaptation driven by oncogenic KRAS signaling. In addition to contributing to KRAS-driven tumorigenesis, I also discovered that NADK plays an essential role in the metastatic cascade in TNBC, powering NADP(H) levels necessary for metastatic initiation and colonization. Together this work demonstrates the importance of de novo NADP+ synthesis, through the activity of NADK, for the different stages of the tumorigenic process and gives rise to the idea that NADK might constitute an important new therapeutic target for hard-to-treat cancers including PDAC and metastatic TNBC.
Metastasis is the leading cause of cancer mortality. Chromatin remodeling provides the foundation for the cellular reprogramming necessary to drive metastasis. However, little is known about the ...nature of this remodeling and its regulation. Here, we show that metastasis-inducing pathways regulate histone chaperones to reduce canonical histone incorporation into chromatin, triggering deposition of H3.3 variant at the promoters of poor-prognosis genes and metastasis-inducing transcription factors. This specific incorporation of H3.3 into chromatin is both necessary and sufficient for the induction of aggressive traits that allow for metastasis formation. Together, our data clearly show incorporation of histone variant H3.3 into chromatin as a major regulator of cell fate during tumorigenesis, and histone chaperones as valuable therapeutic targets for invasive carcinomas.
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•Metastasis inducers lead to a decline in CAF-1 suppressing canonical H3 incorporation•EMT and metastatic colonization occur as a function of CAF-1 levels•Histone H3.3 variant is essential for tumor progression and aggressive phenotypes•HIRA-mediated H3.3 gap filling induces a pro-metastatic transcriptional reprogramming
Gomes et al. reveal metastatic stimuli reduce histone H3.1/H3.2 deposition on chromatin by suppressing the CAF-1 complex in breast and NSCLC cancer cells, leading to increased incorporation of non-canonical histone H3.3, which in turn induces chromatin remodeling and expression of metastatic genes.
Abstract
Consumption of fructose in the form of high fructose corn syrup is elevated in the western diet, but it is not fully understood how fructose metabolism influences anti-tumor immunity. ...Fructose is canonically metabolized in the intestine and the liver and can shunt into glycolysis. In certain tumor types, fructose metabolism becomes deregulated, allowing tumor cells to metabolize fructose to power their biosynthetic processes. Similarly, reprogramming immune cells to be able to efficiently metabolize fructose may help us power immunotherapy to work in difficult to treat cancers, especially in individuals who have high fructose in their blood or in the tumor microenvironment (TME). Imparting effector T cells with the ability to use fructose for fuel can overcome one of the major metabolic limitations of the TME: limited nutrient supply. As T cells become activated, they alter their metabolism to support growth and proliferation. Activated CD8+ T cells upregulate their glycolysis which results in increased biosynthetic processes, such as synthesis of macromolecules and effector cytokines. However, tumor cells also consume substantial amounts of glucose, resulting in a glucose-depleted microenvironment, which could be one of the major barriers to immunotherapy working in solid tumors. Therefore, we engineered T cells to overexpress a fructose transporter, GLUT5, which is normally not expressed in the immune compartment at high levels. We hypothesized that increased fructose uptake by CD8+ T cells will ameliorate exhaustion caused by the glucose-low tumor microenvironment. Indeed, we determined that GLUT5 T cells are more efficient in killing in low glucose supplemented with fructose. We also observed that GLUT5 expression restores T cell glycolytic capacity under fructose to that of unexhausted T cells under glucose replete conditions. Similarly, GLUT5-expressing T cells proliferate faster in vitro and exhibit an improved ability to control B16 tumor growth in vivo. Additionally, combining GLUT5 cell infusion with checkpoint inhibition resulted in durable tumor control and prolonged mouse survival. Further, engineered CD19-targeted CAR T cells with expression of GLUT5 were more metabolically active and cytotoxic in low glucose conditions, mimicking the TME. In conclusion, GLUT5 expression in effector CD8+ and CAR T cells may allow immunotherapy to function in solid tumors under low glucose conditions.
Citation Format: Tanya Schild, Rachel Chirayil, Lyric Haughton, Patrick Wallisch, Marjan Berishaj, David A. Scheinberg, Kayvan R. Keshari. Utilizing fructose metabolism to fuel anti-tumor immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3610.
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