The importance of serine metabolism in cancer Mattaini, Katherine R; Sullivan, Mark R; Vander Heiden, Matthew G
The Journal of cell biology,
08/2016, Letnik:
214, Številka:
3
Journal Article
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Serine metabolism is frequently dysregulated in cancers; however, the benefit that this confers to tumors remains controversial. In many cases, extracellular serine alone is sufficient to support ...cancer cell proliferation, whereas some cancer cells increase serine synthesis from glucose and require de novo serine synthesis even in the presence of abundant extracellular serine. Recent studies cast new light on the role of serine metabolism in cancer, suggesting that active serine synthesis might be required to facilitate amino acid transport, nucleotide synthesis, folate metabolism, and redox homeostasis in a manner that impacts cancer.
Tumors exhibit altered metabolism compared to normal tissues. Many cancers upregulate expression of serine synthesis pathway enzymes, and some tumors exhibit copy-number gain of the gene encoding the ...first enzyme in the pathway, phosphoglycerate dehydrogenase (PHGDH). However, whether increased serine synthesis promotes tumor growth and how serine synthesis benefits tumors is controversial. Here, we demonstrate that increased PHGDH expression promotes tumor progression in mouse models of melanoma and breast cancer, human tumor types that exhibit PHGDH copy-number gain. We measure circulating serine levels and find that PHGDH expression is necessary to support cell proliferation at lower physiological serine concentrations. Increased dietary serine or high PHGDH expression is sufficient to increase intracellular serine levels and support faster tumor growth. Together, these data suggest that physiological serine availability restrains tumor growth and argue that tumors arising in serine-limited environments acquire a fitness advantage by upregulating serine synthesis pathway enzymes.
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•PHGDH expression accelerates mouse models of melanoma and breast cancer•Physiological serine levels can restrain tumor growth in breast cancer•Increased dietary serine levels can accelerate tumor progression•PHGDH expression only benefits tumors in tissues with low serine availability
Nutrient availability can constrain tumor growth. Sullivan et al. demonstrate that in some cancers, physiological levels of the amino acid serine are insufficient to support maximal tumor growth and that melanoma and breast tumors derive a growth advantage by upregulating serine biosynthesis.
Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand ...tumor metabolism. To measure the extracellular nutrient levels available to tumors, we utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.
Person‐centred shared decision making Tonelli, Mark R.; Sullivan, Mark D.
Journal of evaluation in clinical practice,
December 2019, 2019-Dec, 2019-12-00, 20191201, Letnik:
25, Številka:
6
Journal Article
Recenzirano
While multiple versions of shared decision making (SDM) have been advanced, most share two seemingly essential elements: (a) SDM is primarily focused on treatment choices and (b) the clinician is ...primarily responsible for providing options while the patient contributes values and preferences. We argue that these two elements render SDM suboptimal for clinical practice. We suggest that SDM is better viewed as collaboration in all aspects of clinical care, with clinicians needing to fully engage with the patient's experience of illness and participation in treatment. SDM can only take place within an ongoing partnership between clinician and patient, both respecting the other as a person, not as part of an isolated encounter. Respect for the patient as a person goes beyond respect for their choice. Non‐interference is not the only way, or even the most important way, to respect patient autonomy. Knowing the patient as a person and providing an autonomy‐supportive context for care are crucial. That is, the clinician must know the patient well enough to be able to answer the patient's question “What would you do, if you were me?” This approach acknowledges clinicians as persons, requiring them to understand patients as persons. We provide examples of such a model of SDM and assert that this pragmatic method does not require excessive time or effort on the part of clinicians or patients but does require direct and particular knowledge of the patient that is often omitted from clinical decisions.
The role of phosphoglycerate dehydrogenase (PHGDH), a key enzyme of the serine synthesis pathway (SSP), in endothelial cells (ECs) remains poorly characterized. We report that mouse neonates with ...EC-specific PHGDH deficiency suffer lethal vascular defects within days of gene inactivation, due to reduced EC proliferation and survival. In addition to nucleotide synthesis impairment, PHGDH knockdown (PHGDHKD) caused oxidative stress, due not only to decreased glutathione and NADPH synthesis but also to mitochondrial dysfunction. Electron transport chain (ETC) enzyme activities were compromised upon PHGDHKD because of insufficient heme production due to cellular serine depletion, not observed in other cell types. As a result of heme depletion, elevated reactive oxygen species levels caused EC demise. Supplementation of hemin in PHGDHKD ECs restored ETC function and rescued the apoptosis and angiogenesis defects. These data argue that ECs die upon PHGDH inhibition, even without external serine deprivation, illustrating an unusual importance of serine synthesis for ECs.
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•PHGDH loss in endothelial cells causes lethal angiogenesis defects•PHGDH inhibition impairs heme synthesis and reduces purine and pyrimidine synthesis•Heme deficiency causes mitochondrial respiration defects and lethal oxidative stress•Hemin supplementation rescues loss of PHGDH in endothelial cells
Vandekeere et al. highlight a unique role for serine metabolism in endothelial cells (ECs). ECs utilize the serine synthetic pathway (SSP) differently from cancer cells and rely exclusively on the SSP for heme synthesis to maintain mitochondrial respiration and homeostasis.
Influenza prophylaxis would benefit from a vaccination method enabling simplified logistics and improved immunogenicity without the dangers posed by hypodermic needles. Here we introduce dissolving ...microneedle patches for influenza vaccination using a simple patch-based system that targets delivery to skin's antigen-presenting cells. Microneedles were fabricated using a biocompatible polymer encapsulating inactivated influenza virus vaccine for insertion and dissolution in the skin within minutes. Microneedle vaccination generated robust antibody and cellular immune responses in mice that provided complete protection against lethal challenge. Compared to conventional intramuscular injection, microneedle vaccination resulted in more efficient lung virus clearance and enhanced cellular recall responses after challenge. These results suggest that dissolving microneedle patches can provide a new technology for simpler and safer vaccination with improved immunogenicity that could facilitate increased vaccination coverage.
Determinants of nutrient limitation in cancer Sullivan, Mark R.; Vander Heiden, Matthew G.
Critical reviews in biochemistry and molecular biology,
05/2019, Letnik:
54, Številka:
3
Journal Article
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Proliferation requires that cells accumulate sufficient biomass to grow and divide. Cancer cells within tumors must acquire a variety of nutrients, and tumor growth slows or stops if necessary ...metabolites are not obtained in sufficient quantities. Importantly, the metabolic demands of cancer cells can be different from those of untransformed cells, and nutrient accessibility in tumors is different than in many normal tissues. Thus, cancer cell survival and proliferation may be limited by different metabolic factors than those that are necessary to maintain noncancerous cells. Understanding the variables that dictate which nutrients are critical to sustain tumor growth may identify vulnerabilities that could be used to treat cancer. This review examines the various cell-autonomous, local, and systemic factors that determine which nutrients are limiting for tumor growth.
Nearly 90% of human melanomas contain inactivated wild-type p53, the underlying mechanisms for which are not fully understood. Here, we identify that cyclin B1/CDK1-phosphorylates iASPP, which leads ...to the inhibition of iASPP dimerization, promotion of iASPP monomer nuclear entry, and exposure of its p53 binding sites, leading to increased p53 inhibition. Nuclear iASPP is enriched in melanoma metastasis and associates with poor patient survival. Most wild-type p53-expressing melanoma cell lines coexpress high levels of phosphorylated nuclear iASPP, MDM2, and cyclin B1. Inhibition of MDM2 and iASPP phosphorylation with small molecules induced p53-dependent apoptosis and growth suppression. Concurrent p53 reactivation and BRAFV600E inhibition achieved additive suppression in vivo, presenting an alternative for melanoma therapy.
► Cyclin B1/CDK1-phosphorylated nuclear iASPP inhibits p53. ► Cyclin B1/CDK1-phosphorylated nuclear iASPP associates with melanoma metastasis. ► p53 is reactivated by inhibition of iASPP and MDM2 in melanoma cells. ► p53 reactivation cooperates with BRAFV600E blockade to suppress melanoma cell growth
A new room‐temperature, in situ polymerization process to produce microneedles (see figure), which can encapsulate functional biomolecules and dissolve within minutes, is presented. The dissolution ...rate and mechanical strength of these polymer microneedles can be tailored by changing monomer composition and microneedle geometry. Drug delivery using micrometer‐scale needles that dissolve in the skin could eliminate the pain and dangers of hypodermic needle use.
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths in the United States. The deoxynucleoside analogue gemcitabine is among the most effective therapies to treat PDAC, ...however, nearly all patients treated with gemcitabine either fail to respond or rapidly develop resistance. One hallmark of PDAC is a striking accumulation of stromal tissue surrounding the tumor, and this accumulation of stroma can contribute to therapy resistance. To better understand how stroma limits response to therapy, we investigated cell-extrinsic mechanisms of resistance to gemcitabine. Conditioned media from pancreatic stellate cells (PSC), as well as from other fibroblasts, protected PDAC cells from gemcitabine toxicity. The protective effect of PSC-conditioned media was mediated by secretion of deoxycytidine, but not other deoxynucleosides, through equilibrative nucleoside transporters. Deoxycytidine inhibited the processing of gemcitabine in PDAC cells, thus reducing the effect of gemcitabine and other nucleoside analogues on cancer cells. These results suggest that reducing deoxycytidine production in PSCs may increase the efficacy of nucleoside analog therapies. SIGNIFICANCE: This study provides important new insight into mechanisms that contribute to gemcitabine resistance in PDAC and suggests new avenues for improving gemcitabine efficacy.
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