Abstract:
:Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue. :Tumors contain a mixture of many different types of cells, including cancer cells and non-cancer cells. The interactions between these two groups of cells affect how the cancer cells use nutrients, which, in turn, affects how fast these cells grow and divide. Furthermore, different cell types may use nutrients in diverse ways to make other molecules – known as metabolites – that the cell needs to survive. Fibroblasts are a subset of non-cancer cells that are typically found in tumors and can help them form. Separating fibroblasts from cancer cells in a tumor takes a lot longer than the chemical reactions in each cell of the tumor that produce and use up nutrients, also known as the cell’s metabolism. Therefore, measuring the levels of glucose (the sugar that is the main energy source for cells) and other metabolites in each tumor cell after separating them does not necessarily provide accurate information about the tumor cell’s metabolism. This makes it difficult to study how cancer cells and fibroblasts use nutrients differently. Lau et al. have developed a strategy to study the metabolism of cancer cells and fibroblasts in tumors. Mice with tumors in their pancreas were provided glucose that had been labelled using biochemical techniques. As expected, when the cell processed the glucose, the label was transferred into metabolites that got used up very quickly. But the label also became incorporated into larger, more stable molecules, such as proteins. Unlike the small metabolites, these larger molecules do not change in the time it takes to separate the cancer cells from the fibroblasts. Lau et al. sorted cells from whole pancreatic tumors and analyzed large, stable molecules that can incorporate the label from glucose in cancer cells and fibroblasts. The experiments showed that, in cancer cells, these molecules were more likely to have labeling patterns that are characteristic of two specific enzymes called pyruvate carboxylase and malic enzyme 1. This suggests that these enzymes are more active in cancer cells. Lau et al. also found that pancreatic cancer cells needed these two enzymes to metabolize glucose and to grow into large tumors. Pancreatic cancer is one of the most lethal cancers and current therapies offer limited benefit to many patients. Therefore, it is important to develop new drugs to treat this disease. Understanding how cancer cells and non-cancer cells in pancreatic tumors use nutrients differently is important for developing drugs that only target cancer cells.
journal_name
Elifejournal_title
eLifeauthors
Lau AN,Li Z,Danai LV,Westermark AM,Darnell AM,Ferreira R,Gocheva V,Sivanand S,Lien EC,Sapp KM,Mayers JR,Biffi G,Chin CR,Davidson SM,Tuveson DA,Jacks T,Matheson NJ,Yilmaz O,Vander Heiden MGdoi
10.7554/eLife.56782subject
Has Abstractpub_date
2020-07-10 00:00:00issn
2050-084Xpii
56782journal_volume
9pub_type
杂志文章相关文献
eLife文献大全abstract::Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis rev...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.16220
更新日期:2016-07-29 00:00:00
abstract::Microtubules control different aspects of cell polarization. In cells with a radial microtubule system, a pivotal role in setting up asymmetry is attributed to the relative positioning of the centrosome and the nucleus. Here, we show that centrosome loss had no effect on the ability of endothelial cells to polarize an...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.33864
更新日期:2018-03-16 00:00:00
abstract::MyD88 is the main adaptor molecule for TLR and IL-1R family members. Here, we demonstrated that T-cell intrinsic MyD88 signaling is required for proliferation, protection from apoptosis and expression of activation/memory genes during infection with the intracellular parasite Trypanosoma cruzi, as evidenced by transcr...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.30883
更新日期:2017-09-12 00:00:00
abstract::Humans and other animals base important decisions on estimates of number, and intraparietal cortex is thought to provide a crucial substrate of this ability. However, it remains debated whether an independent neuronal processing mechanism underlies this 'number sense', or whether number is instead judged indirectly on...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.45160
更新日期:2019-07-24 00:00:00
abstract::The expansion of bacterial swarms and the spreading of biofilms can be described by a unified biophysical theory that involves both active and passive processes. ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.47019
更新日期:2019-04-30 00:00:00
abstract::CRISPR-based homing gene drives have sparked both enthusiasm and deep concerns due to their potential for genetically altering entire species. This raises the question about our ability to prevent the unintended spread of such drives from the laboratory into a natural population. Here, we experimentally demonstrate th...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.41439
更新日期:2019-01-22 00:00:00
abstract::Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneou...
journal_title:eLife
pub_type: 杂志文章,多中心研究
doi:10.7554/eLife.15085
更新日期:2017-01-09 00:00:00
abstract::Social rank differentially influences how male and female mice respond to chronic stress. ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.63996
更新日期:2020-11-20 00:00:00
abstract::Processing bodies (PBs) are cytoplasmic mRNP granules that assemble via liquid-liquid phase separation and are implicated in the decay or storage of mRNAs. How PB assembly is regulated in cells remains unclear. Previously, we identified the ATPase activity of the DEAD-box protein Dhh1 as a key regulator of PB dynamics...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.41415
更新日期:2019-01-16 00:00:00
abstract::Hawaiian isolates of the nematode species Caenorhabditis elegans have long been known to harbor genetic diversity greater than the rest of the worldwide population, but this observation was supported by only a small number of wild strains. To better characterize the niche and genetic diversity of Hawaiian C. elegans a...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.50465
更新日期:2019-12-03 00:00:00
abstract::The characteristics of goal-directed actions tend to resemble those of previously executed actions, but it is unclear whether such effects depend strictly on action history, or also reflect context-dependent processes related to predictive motor planning. Here we manipulated the time available to initiate movements af...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.26713
更新日期:2017-10-23 00:00:00
abstract::D2 autoreceptors regulate dopamine release throughout the brain. Two isoforms of the D2 receptor, D2S and D2L, are expressed in midbrain dopamine neurons. Differential roles of these isoforms as autoreceptors are poorly understood. By virally expressing the isoforms in dopamine neurons of D2 receptor knockout mice, th...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.09358
更新日期:2015-08-26 00:00:00
abstract::Follicle rupture, the final step in ovulation, utilizes conserved molecular mechanisms including matrix metalloproteinases (Mmps), steroid signaling, and adrenergic signaling. It is still unknown how follicles become competent for follicle rupture/ovulation. Here, we identify a zinc-finger transcription factor Hindsig...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.29887
更新日期:2017-12-19 00:00:00
abstract::Nutritional regulation by ants emerges from a distributed process: food is collected by a small fraction of workers, stored within the crops of individuals, and spread via local ant-to-ant interactions. The precise individual-level underpinnings of this collective regulation have remained unclear mainly due to difficu...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.31730
更新日期:2018-03-06 00:00:00
abstract::The genome-scale transcriptional programs that specify the mammalian trachea and esophagus are unknown. Though NKX2-1 and SOX2 are hypothesized to be co-repressive master regulators of tracheoesophageal fates, this is untested at a whole transcriptomic scale and their downstream networks remain unidentified. By combin...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.55526
更新日期:2020-06-09 00:00:00
abstract::Human lung adenocarcinoma exhibits a propensity for de-differentiation, complicating diagnosis and treatment, and predicting poorer patient survival. In genetically engineered mouse models of lung cancer, expression of the BRAFV600E oncoprotein kinase initiates the growth of benign tumors retaining characteristics of ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.43668
更新日期:2019-08-27 00:00:00
abstract::The >800 human G protein-coupled receptors (GPCRs) are responsible for transducing diverse chemical stimuli to alter cell state- and are the largest class of drug targets. Their myriad structural conformations and various modes of signaling make it challenging to understand their structure and function. Here, we devel...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.54895
更新日期:2020-10-21 00:00:00
abstract::IRE1α is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1α forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (Plumb et al., 2015). Here, we probe IRE1α complexes in...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.27187
更新日期:2017-05-15 00:00:00
abstract::The sequential activation of neurons has been observed in various areas of the brain, but in no case is the underlying network structure well understood. Here we examined the circuit anatomy of zebra finch HVC, a cortical region that generates sequences underlying the temporal progression of the song. We combined seri...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.24364
更新日期:2017-03-27 00:00:00
abstract::The sense of ownership of one's body is important for survival, e.g., in defending the body against a threat. However, in addition to affecting behavior, it also affects perception of the world. In the case of visuospatial perception, it has been shown that the sense of ownership causes external space to be perceptual...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.26022
更新日期:2017-08-17 00:00:00
abstract::Meiotic crossovers result from homology-directed repair of DNA double-strand breaks (DSBs). Unlike yeast and plants, where DSBs are generated near gene promoters, in many vertebrates DSBs are enriched at hotspots determined by the DNA binding activity of the rapidly evolving zinc finger array of PRDM9 (PR domain zinc ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.53360
更新日期:2020-04-30 00:00:00
abstract::Recent lineage tracing analyses have significantly improved our understanding of immune system development and highlighted the importance of the different hematopoietic waves. The current challenge is to understand whether these waves interact and whether this affects the function of the immune system. Here we report ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.34890
更新日期:2018-07-11 00:00:00
abstract::The neural control of sugar consumption is critical for normal metabolism. In contrast to sugar-sensing taste neurons that promote consumption, we identify a taste neuron that limits sucrose consumption in Drosophila. Silencing of the neuron increases sucrose feeding; optogenetic activation decreases it. The feeding i...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.24992
更新日期:2017-03-23 00:00:00
abstract::The permeability barrier of nuclear pore complexes (NPCs) controls bulk nucleocytoplasmic exchange. It consists of nucleoporin domains rich in phenylalanine-glycine motifs (FG domains). As a bottom-up nanoscale model for the permeability barrier, we have used planar films produced with three different end-grafted FG d...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.14119
更新日期:2016-04-08 00:00:00
abstract::Humans and animals construct internal models of their environment in order to select appropriate courses of action. The representation of uncertainty about the current state of the environment is a key feature of these models that controls the rate of learning as well as directly affecting choice behaviour. To maintai...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.39404
更新日期:2019-02-28 00:00:00
abstract::How does the skeleton detect and adapt to changes in the mechanical load it has to carry? ...
journal_title:eLife
pub_type: 评论,杂志文章
doi:10.7554/eLife.50210
更新日期:2019-10-07 00:00:00
abstract::Islet amyloidosis by IAPP contributes to pancreatic β-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat IN...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.12977
更新日期:2016-05-23 00:00:00
abstract::Rod and cone photoreceptors are highly similar in many respects but they have important functional and molecular differences. Here, we investigate genome-wide patterns of DNA methylation and chromatin accessibility in mouse rods and cones and correlate differences in these features with gene expression, histone marks,...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.11613
更新日期:2016-03-07 00:00:00
abstract::Synaptic adhesion molecules regulate synapse development and function. However, whether and how presynaptic adhesion molecules regulate postsynaptic NMDAR function remains largely unclear. Presynaptic LAR family receptor tyrosine phosphatases (LAR-RPTPs) regulate synapse development through mechanisms that include tra...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.54224
更新日期:2020-03-06 00:00:00
abstract::Some DNA viruses overcome plant defenses by producing a suppressor protein that blocks the silencing of viral genes. ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.11509
更新日期:2015-10-16 00:00:00