bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2020‒12‒27
forty papers selected by
Kıvanç Görgülü
Technical University of Munich

  1. Elife. 2020 Dec 21. pii: e63835. [Epub ahead of print]9
      Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote expression of ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning b-oxidation, reflected by increased acylcarnitines and reduced b-hydroxybutyrate. This led to elevated plasma free fatty acids, which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here we demonstrate that loss of hepatocyte proliferation is not only an outcome but possibly causative for liver pathology.
    Keywords:  cell biology; medicine; mouse
  2. Cell Metab. 2020 Dec 09. pii: S1550-4131(20)30604-5. [Epub ahead of print]
      Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin 43 (Cx43)-mediated intercellular communication has been implicated in tissue-adaptive and -maladaptive response to various chronic stresses. Here, we demonstrate that in hepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-culture of ER-stressed "donor" cells resulted in intercellular transmission of ERS and dysfunction to ERS-naive "recipient" cells ("bystander response"), which could be prevented by genetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were able to transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protected from diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling allows intercellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism.
    Keywords:  connexin 43; diabetes; endoplasmic reticulum stress; gap junctions; insulin resistance; intercellular communication; unfolded protein response
  3. J Physiol. 2020 Dec 21.
      Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary, permanent and universal consequence of dysfunctional/impaired mitochondria compensating for poor ATP-yield per mole of glucose. Instead, in most tumours the Warburg effect is an essential part of a "selfish" metabolic reprogramming, which results from the interplay between (normoxic/hypoxic) HIF-1-overexpression, oncogene activation (cMyc, Ras), loss of function of tumour suppressors (mutant-p53, mutant-PTEN, microRNAs and sirtuins with suppressor functions), activated (PI3K/Akt/mTORC1, Ras/Raf/Mek/Erk/cMyc, Jak/Stat3) or deactivated (LKB1/AMPK) signalling pathways, components of the tumour microenvironment, and HIF-1-cooperations with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include: (a) considerably accelerated glycolytic fluxes, (b) adequate ATP generation per unit time to maintain energy homeostasis and electrochemical gradients, (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, non-essential amino acids, lipids and hexosamines, (d) inhibition of pyruvate entry into mitochondria, (e) excessive formation and accumulation of lactate which stimulates tumour growth and suppression of anti-tumour immunity; in addition, lactate can serve as an energy source for normoxic cancer cells and drives malignant progression and resistances to conventional therapies, (f) cytosolic lactate is mainly exported through upregulated lactate-proton symporters (MCT4), working together with other H+ -transporters, and carbonic anhydrases (CAII, CAIX) which hydrate CO2 from oxidative metabolism to form H+ and bicarbonate, (g) in concert with poor vascular drainage these proton export mechanisms are responsible for extracellular acidification, driving malignant progression and resistances to conventional therapies, (h) maintenance of the cellular redox homeostasis and low ROS formation, and (i) HIF-1 overexpression, mutant-p53 and mutant-PTEN which inhibit mitochondrial biogenesis and functions, negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e., aerobic glycolysis in the presence of oxygen and -in principle- functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and poor patient outcome. However, as evidenced during the last two decades, in a minority of tumours primary mitochondrial defects can play a key role promoting the Warburg effect and tumour progression due to mutations in some Krebs cycle enzymes and mitochondrial ROS overproduction. Abstract figure legend Driving processes causing the Warburg effect during carcinogenesis (upper part), and mechanisms/consequences of metabolic reprogramming in Warburg phenotypes (lower part) leading to survival advantages, malignant progression and, ultimately, poor patient outcome. This article is protected by copyright. All rights reserved.
    Keywords:  Warburg effect; aerobic glycolysis; glycolytic phenotype; lactate accumulation; metabolic reprogramming; tumour acidosis; tumour glucose metabolism; tumour mitochondria
  4. Mol Cell. 2020 Dec 10. pii: S1097-2765(20)30836-4. [Epub ahead of print]
      Mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and proliferation by sensing fluctuations in environmental cues such as nutrients, growth factors, and energy levels. The Rag GTPases (Rags) serve as a critical module that signals amino acid (AA) availability to modulate mTORC1 localization and activity. Recent studies have demonstrated how AAs regulate mTORC1 activity through Rags. Here, we uncover an unconventional pathway that activates mTORC1 in response to variations in threonine (Thr) levels via mitochondrial threonyl-tRNA synthetase TARS2. TARS2 interacts with inactive Rags, particularly GTP-RagC, leading to increased GTP loading of RagA. mTORC1 activity in cells lacking TARS2 is resistant to Thr repletion, showing that TARS2 is necessary for Thr-dependent mTORC1 activation. The requirement of TARS2, but not cytoplasmic threonyl-tRNA synthetase TARS, for this effect demonstrates an additional layer of complexity in the regulation of mTORC1 activity.
    Keywords:  Rag GTPases; TARS2; amino acid; aminoacyl-tRNA synthetase; mTORC1; threonine
  5. Cancers (Basel). 2020 Dec 17. pii: E3816. [Epub ahead of print]12(12):
      Purpose: Pancreatic ductal adenocarcinoma (PDAC) has the lowest five-year survival rate of all cancers in the United States. Programmed death 1 receptor (PD-1)-programmed death ligand 1 (PD-L1) immune checkpoint inhibition has been unsuccessful in clinical trials. Myeloid-derived suppressor cells (MDSCs) are known to block anti-tumor CD8+ T cell immune responses in various cancers including pancreas. This has led us to our objective that was to develop a clinically relevant in vitro organoid model to specifically target mechanisms that deplete MDSCs as a therapeutic strategy for PDAC. Method: Murine and human pancreatic ductal adenocarcinoma (PDAC) autologous organoid/immune cell co-cultures were used to test whether PDAC can be effectively treated with combinatorial therapy involving PD-1 inhibition and MDSC depletion. Results: Murine in vivo orthotopic and in vitro organoid/immune cell co-culture models demonstrated that polymorphonuclear (PMN)-MDSCs promoted tumor growth and suppressed cytotoxic T lymphocyte (CTL) proliferation, leading to diminished efficacy of checkpoint inhibition. Mouse- and human-derived organoid/immune cell co-cultures revealed that PD-L1-expressing organoids were unresponsive to nivolumab in vitro in the presence of PMN-MDSCs. Depletion of arginase 1-expressing PMN-MDSCs within these co-cultures rendered the organoids susceptible to anti-PD-1/PD-L1-induced cancer cell death. Conclusions: Here we use mouse- and human-derived autologous pancreatic cancer organoid/immune cell co-cultures to demonstrate that elevated infiltration of polymorphonuclear (PMN)-MDSCs within the PDAC tumor microenvironment inhibit T cell effector function, regardless of PD-1/PD-L1 inhibition. We present a pre-clinical model that may predict the efficacy of targeted therapies to improve the outcome of patients with this aggressive and otherwise unpredictable malignancy.
    Keywords:  PD-L1; myeloid derived suppressor cells (MDSCs); organoid/immune-cell co-culture; organoids; pancreatic ductal adenocarcinoma (PDAC)
  6. Trends Cell Biol. 2020 Dec 18. pii: S0962-8924(20)30245-2. [Epub ahead of print]
      Mesenchymal-epithelial crosstalk plays a crucial role in organ development and stem cell function. However, the identity of the mesenchymal cells involved in this exchange was unclear. Recent significant advances in single-cell transcriptomics have defined the heterogeneity of these mesenchymal niches. By combining multiomic profiling, animal models, and organoid culture, new studies have not only demonstrated the roles of diverse mesenchymal cell populations but also defined the mechanisms underlying their regulation of niche signals. Focusing on several digestive organs, we describe how similar and diverse mesenchymal cell populations promote organ development and maintain proper stem cell activity, and how the heterogeneity of mesenchymal niches is altered in digestive diseases such as inflammation and cancer.
    Keywords:  cancer; digestive organ development; inflammation; single-cell analysis; stem cell niche
  7. J Cachexia Sarcopenia Muscle. 2020 Dec 22.
      BACKGROUND: Cancer cachexia is a debilitating metabolic syndrome contributing to cancer death. Organs other than the muscle may contribute to the pathogenesis of cancer cachexia. This work explores new mechanisms underlying hepatic alterations in cancer cachexia.METHODS: We used transcriptomics to reveal the hepatic gene expression profile in the colon carcinoma 26 cachectic mouse model. We performed bile acid, tissue mRNA, histological, biochemical, and western blot analyses. Two interventional studies were performed using a neutralizing interleukin 6 antibody and a bile acid sequestrant, cholestyramine. Our findings were evaluated in a cohort of 94 colorectal cancer patients with or without cachexia (43/51).
    RESULTS: In colon carcinoma 26 cachectic mice, we discovered alterations in five inflammatory pathways as well as in other pathways, including bile acid metabolism, fatty acid metabolism, and xenobiotic metabolism (normalized enrichment scores of -1.97, -2.16, and -1.34, respectively; all Padj < 0.05). The hepatobiliary transport system was deeply impaired in cachectic mice, leading to increased systemic and hepatic bile acid levels (+1512 ± 511.6 pmol/mg, P = 0.01) and increased hepatic inflammatory cytokines and neutrophil recruitment to the liver of cachectic mice (+43.36 ± 16.01 neutrophils per square millimetre, P = 0.001). Adaptive mechanisms were set up to counteract this bile acid accumulation by repressing bile acid synthesis and by enhancing alternative routes of basolateral bile acid efflux. Targeting bile acids using cholestyramine reduced hepatic inflammation, without affecting the hepatobiliary transporters (e.g. tumour necrosis factor α signalling via NFκB and inflammatory response pathways, normalized enrichment scores of -1.44 and -1.36, all Padj < 0.05). Reducing interleukin 6 levels counteracted the change in expression of genes involved in the hepatobiliary transport, bile acid synthesis, and inflammation. Serum bile acid levels were increased in cachectic vs. non-cachectic cancer patients (e.g. total bile acids, +5.409 ± 1.834 μM, P = 0.026) and were strongly correlated to systemic inflammation (taurochenodeoxycholic acid and C-reactive protein: ρ = 0.36, Padj = 0.017).
    CONCLUSIONS: We show alterations in bile acid metabolism and hepatobiliary secretion in cancer cachexia. In this context, we demonstrate the contribution of systemic inflammation to the impairment of the hepatobiliary transport system and the role played by bile acids in the hepatic inflammation. This work paves the way to a better understanding of the role of the liver in cancer cachexia.
    Keywords:  Bile acids; Cholestyramine; Hepatobiliary transport system; IL-6; Liver
  8. Genes Chromosomes Cancer. 2020 Dec 20.
      Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Recently, the Poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib has been approved for maintenance therapy after successful platinum-based chemotherapy in patients with germline mutations in BRCA1 and BRCA2. Approval was based on the POLO study that has shown a significant improvement in progression-free survival for patients with metastatic PDAC after at least 4 months of platinum-based chemotherapy. Hopefully, this first biomarker-directed targeted therapy for a relevant subgroup of pancreatic cancer patients is only the beginning of an era of personalized therapy for pancreatic cancer. The potential role for PARPi in improving survival in patients with pancreatic cancer containing somatic tumor mutations has yet to be stablished. Multiple studies investigating whether PARPi therapy might benefit a larger group of pancreatic cancer patients with homologous recombination repair deficiency and whether combinations with chemotherapy, immunotherapy or small molecules can improve efficacy are currently underway. We here review the molecular basis for PARPi therapy in PDAC patients and recent developments in clinical studies. This article is protected by copyright. All rights reserved.
    Keywords:  PARP inhibitor; Pancreatic cancer; olaparib
  9. Trends Cancer. 2020 Dec 16. pii: S2405-8033(20)30329-0. [Epub ahead of print]
      Pancreatic innervation is an important factor in pancreatic cancer etiology and progression. Recent work by Banh et al. has revealed that serine released from the axons of sensory and sympathetic neurons supports pancreatic cancer metabolism during nutrient-deprived conditions. These findings rationalize a therapeutic strategy to combine dietary manipulation and pharmacological denervation to target pancreatic cancer.
    Keywords:  metabolism; neural input; pancreatic cancer; translation
  10. Mol Cell. 2020 Dec 15. pii: S1097-2765(20)30827-3. [Epub ahead of print]
      In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.
    Keywords:  MCT2; PHGDH; breast cancer; lung environment; mTORC1; metastasis formation; pyruvate; serine biosynthesis; α-ketoglutarate
  11. Biochim Biophys Acta Mol Cell Res. 2020 Dec 16. pii: S0167-4889(20)30286-X. [Epub ahead of print] 118928
      Ferroptosis is a necrotic form of cell death caused by inactivation of the glutathione system and uncontrolled iron-mediated lipid peroxidation. Increasing evidence implicates ferroptosis in a wide range of diseases from neurotrauma to cancer, highlighting the importance of identifying an executioner system that can be exploited for clinical applications. In this study, using pharmacological and genetic models of ferroptosis, we observed that lysosomal membrane permeabilization and cytoplasmic leakage of cathepsin B unleashes structural and functional changes in mitochondria and promotes a not previously reported cleavage of histone H3. Inhibition of cathepsin-B robustly rescued cellular membrane integrity and chromatin degradation. We show that these protective effects are independent of glutathione peroxidase-4 and are mediated by preventing lysosomal membrane damage. This was further confirmed when cathepsin B knockout primary fibroblasts remained unaffected in response to various ferroptosis inducers. Our work identifies new and yet-unrecognized aspects of ferroptosis and identifies cathepsin B as a mediator of ferroptotic cell death.
    Keywords:  GPX4; Histone H3; autophagy; glutathione; lipid peroxidation; lysosomes
  12. Matrix Biol. 2020 Dec 13. pii: S0945-053X(20)30118-9. [Epub ahead of print]
      The conserved catabolic process of autophagy is an important control mechanism that degrades cellular organelles, debris and pathogens in autolysosomes. Although autophagy primarily protects against cellular insults, nutrient starvation or oxidative stress, hyper-activation of autophagy is also believed to cause autophagy-dependent cell death (ADCD). ADCD is a caspase-independent form of programmed cell death (PCD), characterized by an over-activation of autophagy, leading to prominent self-digestion of cellular material in autolysosomes beyond the point of cell survival. ADCD plays important roles in the development of lower organisms, but also in the response of cancer cells upon exposure of specific drugs or natural compounds. Importantly, the induction of ADCD as an alternative cell death pathway is of special interest in apoptosis-resistant cancer types and serves as an attractive and potential therapeutic option. Although the mechanisms of ADCD are diverse and not yet fully understood, both non-selective (bulk) autophagy and organelle-specific types of autophagy are believed to be involved in this type of cell death. Accordingly, several ADCD-inducing drugs are known to trigger severe mitochondrial damage and endoplasmic reticulum (ER) stress, whereas the contribution of other cell organelles, like ribosomes or peroxisomes, to the control of ADCD is not well understood. In this review, we highlight the general mechanisms of ADCD and discuss the current evidence for mitochondria- and ER-specific killing mechanisms of ADCD-inducing drugs.
    Keywords:  Autophagy-dependent cell death; ER, ER stress; Mitochondria; Mitophagy
  13. Oncologist. 2020 Dec 20.
      BACKGROUND: We examined overall survival (OS) outcomes based on plasma 25-hydroxyvitamin D (25[OH]D) levels in this post hoc analysis of the phase III MPACT trial of metastatic pancreatic cancer.METHODS: Patients were subdivided based on 25(OH)D level: sufficient (≥ 30 ng/mL), relatively insufficient (20 to < 30 ng/mL), or insufficient (< 20 ng/mL).
    RESULTS: Of 861 patients randomized in MPACT, 422 were included in this analysis. In the all-patients group, the median OS among those with insufficient, relatively insufficient, and sufficient 25(OH)D levels was 7.9, 9.4, and 7.8 months, respectively. No statistically significant OS difference was observed with relatively insufficient (P = .227) or sufficient (P = .740) vs insufficient 25(OH)D levels or with sufficient vs relatively insufficient (P = .301) 25(OH)D levels.
    CONCLUSION: No association was observed between plasma 25(OH)D levels and survival. Further investigations are needed to understand any role of vitamin D in pancreatic cancer.
    Keywords:  Biomarker; gemcitabine; metastatic pancreatic cancer; nab-paclitaxel; plasma vitamin D
  14. JAMA. 2020 Dec 22. 324(24): 2521-2535
      Importance: The number of cancer survivors who develop new cancers is projected to increase, but comprehensive data on the risk of subsequent primary cancers (SPCs) among survivors of adult-onset cancers are limited.Objective: To quantify the overall and cancer type-specific risks of SPCs among adult-onset cancer survivors by first primary cancer (FPC) types and sex.
    Design, Setting, and Participants: A retrospective cohort study from 12 Surveillance, Epidemiology, and End Results registries in the United States, that included 1 537 101 persons aged 20 to 84 years diagnosed with FPCs from 1992-2011 (followed up until December 31, 2017) and who survived at least 5 years.
    Exposures: First primary cancer.
    Main Outcomes and Measures: Incidence and mortality of SPCs per 10 000 person-years; standardized incidence ratio (SIR) and standardized mortality ratio (SMR) compared with those expected in the general population.
    Results: Among 1 537 101 survivors (mean age, 60.4 years; 48.8% women), 156 442 SPC cases and 88 818 SPC deaths occurred during 11 197 890 person-years of follow-up (mean, 7.3 years). Among men, the overall risk of developing any SPCs was statistically significantly higher for 18 of the 30 FPC types, and risk of dying from any SPCs was statistically significantly higher for 27 of 30 FPC types as compared with risks in the general population. Among women, the overall risk of developing any SPCs was statistically significantly higher for 21 of the 31 FPC types, and risk of dying from any SPCs was statistically significantly higher for 28 of 31 FPC types as compared with risks in the general population. The highest overall SIR and SMR were estimated among survivors of laryngeal cancer (SIR, 1.75 [95% CI, 1.68-1.83]; incidence, 373 per 10 000 person-years) and gallbladder cancer (SMR, 3.82 [95% CI, 3.31-4.39]; mortality, 341 per 10 000 person-years) among men, and among survivors of laryngeal cancer (SIR, 2.48 [95% CI, 2.27-2.72]; incidence, 336 per 10 000 person-years; SMR, 4.56 [95% CI, 4.11-5.06]; mortality, 268 per 10 000 person-years) among women. Substantial variation existed in the associations of specific types of FPCs with specific types of SPC risk; however, only a few smoking- or obesity-associated SPCs, such as lung, urinary bladder, oral cavity/pharynx, colorectal, pancreatic, uterine corpus, and liver cancers constituted considerable proportions of the total incidence and mortality, with lung cancer alone accounting for 31% to 33% of mortality from all SPCs.
    Conclusions and Relevance: Among survivors of adult-onset cancers in the United States, several types of primary cancer were significantly associated with greater risk of developing and dying from an SPC, compared with the general population. Cancers associated with smoking or obesity comprised substantial proportions of overall SPC incidence and mortality among all survivors and highlight the importance of ongoing surveillance and efforts to prevent new cancers among survivors.
  15. Trends Biochem Sci. 2020 Dec 18. pii: S0968-0004(20)30266-8. [Epub ahead of print]
      Characteristically, cells must sense and respond to environmental cues. Despite the importance of cell-cell communication, our understanding remains limited and often lacks glycans. Glycans decorate proteins and cell membranes at the cell-environment interface, and modulate intercellular communication, from development to pathogenesis. Providing further challenges, glycan biosynthesis and cellular behavior are co-regulating systems. Here, we discuss how glycosylation contributes to extracellular responses and signaling. We further organize approaches for disentangling the roles of glycans in multicellular interactions using newly available datasets and tools, including glycan biosynthesis models, omics datasets, and systems-level analyses. Thus, emerging tools in big data analytics and systems biology are facilitating novel insights on glycans and their relationship with multicellular behavior.
    Keywords:  bioinformatics; cell–cell interaction; extracellular matrix; glycobiology; glycomics; systems biology
  16. Elife. 2020 Dec 22. pii: e60987. [Epub ahead of print]9
      Essential, conserved cellular processes depend not only on essential, strictly conserved proteins but also on essential proteins that evolve rapidly. To probe this poorly understood paradox, we exploited the rapidly evolving Drosophila telomere-binding protein, cav/HOAP, which protects chromosomes from lethal end-to-end fusions. We replaced the D. melanogaster HOAP with a highly diverged version from its close relative, D. yakuba. The D. yakuba HOAP ('HOAP[yak]') localizes to D. melanogaster telomeres and protects D. melanogaster chromosomes from fusions. However, HOAP[yak] fails to rescue a previously uncharacterized HOAP function: silencing of the specialized telomeric retrotransposons that, instead of telomerase, maintain chromosome length in Drosophila. Whole genome sequencing and cytogenetics of experimentally evolved populations revealed that HOAP[yak] triggers telomeric retrotransposon proliferation, resulting in aberrantly long telomeres. This evolution-generated, separation-of-function allele resolves the paradoxical observation that a fast-evolving essential gene directs an essential, strictly conserved function: telomeric retrotransposon containment, not end-protection, requires evolutionary innovation at HOAP.
    Keywords:  D. melanogaster; conflict; domestication; essential gene; evolutionary biology; positive selection; retrotransposon; telomere
  17. Cell. 2020 Dec 15. pii: S0092-8674(20)31606-8. [Epub ahead of print]
      Health is usually defined as the absence of pathology. Here, we endeavor to define health as a compendium of organizational and dynamic features that maintain physiology. The biological causes or hallmarks of health include features of spatial compartmentalization (integrity of barriers and containment of local perturbations), maintenance of homeostasis over time (recycling and turnover, integration of circuitries, and rhythmic oscillations), and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, and repair and regeneration). Disruption of any of these interlocked features is broadly pathogenic, causing an acute or progressive derailment of the system coupled to the loss of numerous stigmata of health.
  18. EMBO J. 2020 Dec 21. e106010
      The cochlea encodes sound pressures varying over six orders of magnitude by collective operation of functionally diverse spiral ganglion neurons (SGNs). The mechanisms enabling this functional diversity remain elusive. Here, we asked whether the sound intensity information, contained in the receptor potential of the presynaptic inner hair cell (IHC), is fractionated via heterogeneous synapses. We studied the transfer function of individual IHC synapses by combining patch-clamp recordings with dual-color Rhod-FF and iGluSnFR imaging of presynaptic Ca2+ signals and glutamate release. Synapses differed in the voltage dependence of release: Those residing at the IHC' pillar side activated at more hyperpolarized potentials and typically showed tight control of release by few Ca2+ channels. We conclude that heterogeneity of voltage dependence and release site coupling of Ca2+ channels among the synapses varies synaptic transfer within individual IHCs and, thereby, likely contributes to the functional diversity of SGNs. The mechanism reported here might serve sensory cells and neurons more generally to diversify signaling even in close-by synapses.
    Keywords:  calcium channel; exocytosis; nanodomain; synaptic heterogeneity; wide dynamic range coding
  19. Front Cell Dev Biol. 2020 ;8 545934
      Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) performs essential roles in regulating cancer initiation and progression, but its implication in pancreatic ductal adenocarcinoma (PDAC) requires further elucidation. In this study, asymmetric dimethylarginine (ADMA)-containing peptides in PDAC cell line PANC-1 were identified by label-free quantitative proteomics combined with affinity purification, using human non-cancerous pancreatic ductal epithelium cell line HPDE6c7 as the control. In total, 289 ADMA sites in 201 proteins were identified in HPDE6c7 and PANC-1 cells, including 82 sites with lower dimethylation and 37 sites with higher dimethylation in PANC-1 cells compared with HPDE6c7 cells. These ADMA-containing peptides demonstrated significant enrichment of glycine and proline residues in both cell lines. Importantly, leucine residues were significantly enriched in ADMA-containing peptides identified only in HPDE6c7 cells or showing lower dimethylation in PANC-1 cells. ADMA-containing proteins were significantly enriched in multiple biological processes and signaling cascades associated with cancer development, such as spliceosome machinery, the Wnt/β-catenin, Hedgehog, tumor growth factor beta (TGF-β), and mitogen-activated protein kinase (MAPK) signaling pathways. Moreover, PDAC cell lines with enhanced cell viability showed lower PRMT4 protein abundance and global ADMA-containing protein levels compared with HPDE6c7. PRMT4 overexpression partially recovered ADMA-containing protein levels and repressed viability in PANC-1 cells. These results revealed significantly altered ADMA-containing protein profiles in human pancreatic carcinoma cells, which provided a basis for elucidating the pathogenic roles of PRMT-mediated protein methylation in pancreatic cancer.
    Keywords:  PRMT4; asymmetric dimethylarginine; label-free quantitative proteomics; pancreatic ductal adenocarcinoma; protein methylation
  20. J Cell Mol Med. 2020 Dec 20.
      Pancreatic cancer is a highly malignant tumour of the digestive tract which is difficult to diagnose and treat. Approximately 90% of cases arise from ductal adenocarcinoma of the glandular epithelium. The morbidity and mortality of the disease have increased significantly in recent years. Its 5-year survival rate is <1% and has one of the worst prognoses amongst malignant tumours. Pancreatic cancer has a low rate of early-stage diagnosis, high surgical mortality and low cure rate. Selenium compounds produced by selenoamino acid metabolism may promote a large amount of oxidative stress and subsequent unfolded reactions and endoplasmic reticulum stress by consuming the NADPH in cells, and eventually lead to apoptosis, necrosis or necrotic cell death. In this study, we first identified DIAPH3 as a highly expressed protein in the tissues of patients with pancreatic cancer, and confirmed that DIAPH3 promoted the proliferation, anchorage-independent growth and invasion of pancreatic cancer cells using overexpression and interference experiments. Secondly, bioinformatics data mining showed that the potential proteins interacted with DIAPH3 were involved in selenoamino acid metabolism regulation. Selenium may be incorporated into selenoprotein synthesis such as TrxR1 and GPX4, which direct reduction of hydroperoxides or resist ferroptosis, respectively. Our following validation confirmed that DIAPH3 promoted selenium content and interacted with the selenoprotein RPL6, a ribosome protein subunit involved in selenoamino acid metabolism. In addition, we verified that DIAPH3 could down-regulate cellular ROS level via up-regulating TrxR1 expression. Finally, nude mice xenograft model experimental results demonstrate DIAPH3 knock down could decrease tumour growth and TrxR1 expression and ROS levels in vivo. Collectively, our observations indicate DIAPH3 could promote pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects.
    Keywords:  DIAPH3; Selenoamino Acid Metabolism; TrxR1; pancreatic cancer
  21. J Invest Dermatol. 2020 Dec 18. pii: S0022-202X(20)32284-3. [Epub ahead of print]
      Chronic exposure to UVR is known to disrupt tissue homeostasis, accelerate the onset of age-related phenotypes, and increase the risk for skin cancer-a phenomenon defined as photoaging. In this paper, we review the current knowledge on how UV exposure causes cells to prematurely enter cellular senescence. We describe the mechanisms contributing to the accumulation of senescent cells in the skin and how the persistence of cellular senescence can promote impaired regenerative capacity, chronic inflammation, and tumorigenesis associated with photoaging. We conclude by highlighting the potential of senolytic drugs in delaying the onset and progression of age-associated phenotypes in the skin.
  22. Elife. 2020 Dec 21. pii: e64587. [Epub ahead of print]9
      The skeletal muscle of fruit flies communicates with other organs to prevent the accumulation of too much fat and to protect adults against obesity.
    Keywords:  D. melanogaster; PDGF; VEGF; genetics; genomics; hepatocyte; mTOR; myokine; obesity
  23. Biochem Cell Biol. 2020 Dec 20.
      Mitochondria modify their function and morphology to satisfice the bioenergetic demand of the cells. Cancer cells take advantage of these features to sustain their metabolic, proliferative, metastatic, and survival necessities. Therefore, the understanding of mitochondrial morphologic changes of the different grades of Triple-Negative Breast Cancer (TNBC) could be relevant for the design of novel treatments. Consequently, this research aimed to explore the mitochondria morphology and gene expression of some proteins related to mitochondrial dynamics as well as proteins related to oxidative and non-oxidative metabolism of metastatic and non-metastatic TNBC. We found that mitochondrial-morphology and metabolism are different between metastatic and non-metastatic TNBC. Metastatic TNBC showed overexpression of genes related to mitochondrial dynamics, fatty acids, and glycolytic metabolism. These features were accompanied by a fused mitochondrial morphology. In contrast, the non-metastatic TNBC presented a stress-associated mitochondrial morphology, hyperfragmented mitochondria accompanied by upregulated expression of mitochondrial biogenesis-related genes, both characteristics related to the higher ROS production observed in this cell line. These differences found between metastatic and non-metastatic TNBC will allow a better understanding of the metastasis process and the improvement of the development of a specific and personalized TNBC therapy.
  24. Cancer Lett. 2020 Dec 18. pii: S0304-3835(20)30681-9. [Epub ahead of print]
      The tumour microenvironment is of critical importance in cancer development and progression and includes the surrounding stromal and immune cells, extracellular matrix, and the milieu of metabolites and signalling molecules in the intercellular space. To support sustained mitotic activity cancer cells must reconfigure their metabolic phenotype. Lactate is the major by-product of such metabolic alterations and consequently, accumulates in the tumour. Lactate actively contributes to immune evasion, a hallmark of cancer, by directly inhibiting immune cell cytotoxicity and proliferation. Furthermore, lactate can recruit and induce immunosuppressive cell types, such as regulatory T cells, tumour-associated macrophages, and myeloid-derived suppressor cells which further suppress anti-tumour immune responses. Given its roles in oncogenesis, measuring intratumoural and systemic lactate levels has shown promise as a both predictive and prognostic biomarker in several cancer types. The efficacies of many anti-cancer therapies are limited by an immunosuppressive TME in which lactate is a major contributor, therefore, targeting lactate metabolism is a priority. Developing inhibitors of key proteins in lactate metabolism such as GLUT1, hexokinase, LDH, MCT and HIF have shown promise in preclinical studies, however there is a corresponding lack of success in human trials so far. This may be explained by a weakness of preclinical models that fail to reproduce the complexities of metabolic interactions in natura. The future of these therapies may be as an adjunct to more conventional treatments.
    Keywords:  Immune evasion; Metabolic reprogramming; Oncometabolite; Predictive and prognostic biomarker; Warburg effect
  25. EMBO J. 2020 Dec 22. e105106
      Centriole copy number is tightly maintained by the once-per-cycle duplication of these organelles. Centrioles constitute the core of centrosomes, which organize the microtubule cytoskeleton and form the poles of the mitotic spindle. Centrosome amplification is frequently observed in tumors, where it promotes aneuploidy and contributes to invasive phenotypes. In non-transformed cells, centrosome amplification triggers PIDDosome activation as a protective response to inhibit cell proliferation, but how extra centrosomes activate the PIDDosome remains unclear. Using a genome-wide screen, we identify centriole distal appendages as critical for PIDDosome activation in cells with extra centrosomes. The distal appendage protein ANKRD26 is found to interact with and recruit the PIDDosome component PIDD1 to centriole distal appendages, and this interaction is required for PIDDosome activation following centrosome amplification. Furthermore, a recurrent ANKRD26 mutation found in human tumors disrupts PIDD1 localization and PIDDosome activation in cells with extra centrosomes. Our data support a model in which ANKRD26 initiates a centriole-derived signal to limit cell proliferation in response to centrosome amplification.
    Keywords:  ANKRD26; PIDDosome; centriole; centriole amplification
  26. Nat Nanotechnol. 2020 Dec 21.
      Immunotherapy is known to be clinically beneficial for cancer patients and in many cases represents the new standard of care. Because of this success, the interest in integrating nanomedicine with cancer immunotherapy to further improve clinical response and toxicity profiles has grown. However, unlike conventional systemic therapies, which are directly cytotoxic to tumour cells, cancer immunotherapy relies on the host's immune system to generate tumouricidal effects. As such, proper design of cancer immune nanomedicine requires scrutiny of tumours' intrinsic and extrinsic factors that may impact host antitumour immunity. Here, we highlight key parameters that differentiate cancer immunotherapy from conventional cytotoxic agents, and we discuss their implications for designing preclinical cancer immune nanomedicine studies. We emphasize that these factors, including intratumoural genomic heterogeneity, commensal diversity, sexual dimorphism and biological ageing, which were largely ignored in traditional cancer nanomedicine experiments, should be carefully considered and incorporated into cancer immune nanomedicine investigations given their critical involvement in shaping the body's antitumour immune responses.
  27. EMBO Rep. 2020 Dec 20. e51239
      Metabolic reprogramming of non-cancer cells residing in a tumor microenvironment, as a result of the adaptations to cancer-derived metabolic and non-metabolic factors, is an emerging aspect of cancer-host interaction. We show that in normal and cancer-associated fibroblasts, breast cancer-secreted extracellular vesicles suppress mTOR signaling upon amino acid stimulation to globally reduce mRNA translation. This is through delivery of cancer-derived miR-105 and miR-204, which target RAGC, a component of Rag GTPases that regulate mTORC1 signaling. Following amino acid starvation and subsequent re-feeding, 13 C-arginine labeling of de novo synthesized proteins shows selective translation of proteins that cluster to specific cellular functional pathways. The repertoire of these newly synthesized proteins is altered in fibroblasts treated with cancer-derived extracellular vesicles, in addition to the overall suppressed protein synthesis. In human breast tumors, RAGC protein levels are inversely correlated with miR-105 in the stroma. Our results suggest that through educating fibroblasts to reduce and re-prioritize mRNA translation, cancer cells rewire the metabolic fluxes of amino acid pool and dynamically regulate stroma-produced proteins during periodic nutrient fluctuations.
    Keywords:  breast cancer; extracellular vesicles; mRNA translation; mTORC1; microRNA
  28. Nutr Healthy Aging. 2020 Nov 03. 5(4): 239-246
       As the global population ages, there is increased interest in living longer and improving one's quality of life in later years. However, studying aging - the decline in body function - is expensive and time-consuming. And despite research success to make model organisms live longer, there still aren't really any feasible solutions for delaying aging in humans. With space travel, scientists and engineers couldn't know what it would take to get to the moon. They had to extrapolate from theory and shorter-range tests. Perhaps with aging, we need a similar moonshot philosophy. And though "shot" might imply medicine, perhaps we need to think beyond medical interventions. Like the moon once was, we seem a long way away from provable therapies to increase human healthspan (the healthy period of one's life) or lifespan (how long one lives). This review therefore focuses on radical proposals. We hope it might stimulate discussion on what we might consider doing significantly differently than ongoing aging research.
  29. Lancet. 2021 Dec 19. pii: S0140-6736(20)32706-9. [Epub ahead of print]396(10267): 1950
  30. Pancreatology. 2020 Dec 13. pii: S1424-3903(20)30868-1. [Epub ahead of print]
      Glutathione-S-transferases (GSTs) not only show cytoprotective role and their involvement in the development of anticancer drug resistance, but also transmit signals that control cell proliferation and apoptosis. However, the role of GST isoforms in chemotherapy resistance remains elusive in pancreatic cancer. Here, we demonstrated that gemcitabine treatment increased the GSTM2 expression in pancreatic cancer cell lines. Knockdown of GSTM2 by siRNA elevated apoptosis and decreased viability of pancreatic cancer cells treated with gemcitabine. Moreover, in vivo experiments further showed that shRNA induced GSTM2 downregulation enhanced drug sensitivity of gemcitabine in orthotopic pancreatic tumor mice. We also found that GSTM2 levels were lower in tumor tissues than in non-tumor tissues and higher GSTM2 expression was significantly associated with longer overall survival. In conclusion, our findings indicate that GSTM2 expression is essential for the survival of pancreatic cancer cells undergoing gemcitabine treatment and leads to chemo resistance. Downregulation of GSTM2 in pancreatic cancer may benefit gemcitabine treatment. GSTM2 expression in patients also shows significant correlation with overall survival. Thus, our study suggests that GSTM2 is a potential target for chemotherapy optimization and prognostic biomarker of pancreatic cancer.
    Keywords:  Chemosensitivity; Gemcitabine; Glutathione-S-Transferase M2 (GSTM2); Pancreatic cancer; Prognosis
  31. Biochem J. 2020 Dec 21. pii: BCJ20200705. [Epub ahead of print]
      Human body temperature limits below 40 °C during heat stroke or fever. The implications of prolonged exposure to the physiologically relevant temperature (40 °C) on cellular mechanobiology is poorly understood. Here, we have examined the effects of heat stress (40 °C for 72 h incubation) in human lung adenocarcinoma (A549), mouse melanoma (B16F10), and non-cancerous mouse origin adipose tissue cells (L929). Hyperthermia increased the level of ROS, γ-H2AX, and HSP70 and decreased mitochondrial membrane potential in the cells. Heat stress impaired cell division, caused G1 arrest, induced cellular senescence, and apoptosis in all the tested cell lines. The cells incubated at 40 °C for 72 h displayed a significant decrease in the f-actin level and cellular traction as compared to cells incubated at 37 °C. Also, the cells showed a larger focal adhesion area and stronger adhesion at 40 °C than at 37 °C. The mitotic cells at 40 °C were unable to round up properly and displayed retracting actin stress fibers. Hyperthermia downregulated HDAC6, increased the acetylation level of microtubules, and perturbed the chromosome alignment in the mitotic cells at 40 °C. Overexpression of HDAC6 rescued the cells from the G1 arrest and reduced the delay in cell rounding at 40 °C suggesting a crucial role of HDAC6 in hyperthermia mediated responses. This study elucidates the significant role of cellular traction, focal adhesions, and cytoskeletal networks in mitotic cell rounding and chromosomal misalignment. It also highlights the significance of HDAC6 in heat-evoked senile cellular responses.
    Keywords:  Chromosomal misalignment; HDAC6; Mitotic cell rounding; Prolonged hyperthermia; Traction force; Trypsin deadhesion assay
  32. Trends Cancer. 2020 Dec 16. pii: S2405-8033(20)30308-3. [Epub ahead of print]
      Nuclear receptors are a family of transcription factors localized in cell nuclei, sensing specific ligands and fine-tuning a variety of cell physiological events. They have been intensively investigated in cancer biology. With their excellent properties of druggability and actionability, nuclear receptors have demonstrated much promise as novel therapeutic targets for different cancer types. Accumulating evidence has highlighted the essential roles of certain nuclear receptors in tumor immunology, suggesting the possibility for them to serve as cancer immunotherapeutic targets. Here, we summarize the roles of nuclear receptors in cancer biology and tumor immunology, and underscore the current advances of clinical trials for nuclear receptor-based cancer therapeutics.
    Keywords:  cancer therapy; nuclear receptors; tumor immunology
  33. Lancet. 2021 12 19. pii: S0140-6736(20)32709-4. [Epub ahead of print]396(10267): 1941
  34. Lancet. 2021 Dec 19. pii: S0140-6736(20)32710-0. [Epub ahead of print]396(10267): 1952-1953
  35. Int J Mol Sci. 2020 Dec 17. pii: E9648. [Epub ahead of print]21(24):
      Tumor progression to a metastatic and ultimately lethal stage relies on a tumor-supporting microenvironment that is generated by reciprocal communication between tumor and stromal host cells. The tumor-stroma crosstalk is instructed by the genetic alterations of the tumor cells-the most frequent being mutations in the gene Tumor protein p53 (TP53) that are clinically correlated with metastasis, drug resistance and poor patient survival. The crucial mediators of tumor-stroma communication are tumor-derived extracellular vesicles (EVs), in particular exosomes, which operate both locally within the primary tumor and in distant organs, at pre-metastatic niches as the future sites of metastasis. Here, we review how wild-type and mutant p53 proteins control the secretion, size, and especially the RNA and protein cargo of tumor-derived EVs. We highlight how EVs extend the cell-autonomous tumor suppressive activity of wild-type p53 into the tumor microenvironment (TME), and how mutant p53 proteins switch EVs into oncogenic messengers that reprogram tumor-host communication within the entire organism so as to promote metastatic tumor cell dissemination.
    Keywords:  exosomes; extracellular vesicles; metastatic niche priming; mutant p53; p53; pre-metastatic niche; tumor microenvironment
  36. Nature. 2020 Dec 21.
    Keywords:  Diseases; Epidemiology; Public health; SARS-CoV-2
  37. EBioMedicine. 2020 Dec 16. pii: S2352-3964(20)30550-8. [Epub ahead of print]63 103174
  38. Mol Metab. 2020 Dec 17. pii: S2212-8778(20)30218-0. [Epub ahead of print] 101144
      OBJECTIVES: The skin is the largest sensory organ of the human body, and plays a fundamental role in regulating body temperature, however, adaptive alterations in skin functions and morphology have only vaguely been associated with physiological responses to cold stress or sensation of ambient temperatures. We have previously found that loss of acyl-CoA binding protein (ACBP) in keratinocytes upregulates lipolysis in white adipose tissue and alters hepatic lipid metabolism, suggesting a link between epidermal barrier functions and systemic energy metabolism.METHODS: To disentangle the physiological responses to loss of ACBP in keratinocytes in detail we have used full-body ACBP-/- and skin-specific ACBP-/- knockout mice to clarify how loss of ACBP affects 1) energy expenditure by indirect calorimetry, 2) response to high fat feeding and a high oral glucose load and 3) expression of brown-selective gene programs by quantitative PCR in inguinal WAT (iWAT). To further elucidate the role of the epidermal barrier in systemic energy metabolism, we included mice with defects in skin structural proteins (ma/ma Flgft/ft) in these studies.
    RESULTS: We show that ACBP-/- mice and skin-specific ACBP-/- knockout mice exhibit increased energy expenditure, increased food intake, browning of the iWAT, and resistance to diet-induced obesity. The metabolic phenotype, including browning of the iWAT, is reversed by housing the mice at thermoneutrality (30°C) or by pharmacological β-adrenergic blocking. Interestingly, these findings are phenocopied in flaky tail mice (ma/ma Flgft/ft). Taken together we show that a compromised epidermal barrier induces a β-adrenergic response that increases energy expenditure and browning of the white adipose tissue to maintain a normal body temperature.
    CONCLUSION: Our findings show that the epidermal barrier plays a key role in maintaining systemic metabolic homeostasis. Thus, regulation of epidermal barrier functions warrants further attention to understand regulation of systemic metabolism in further detail.
    Keywords:  Epidermal barrier; acyl-CoA binding protein; adipose tissue; browning; diet induced obesity; energy expenditure; filaggrin; β-adrenergic signaling