bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒07‒17
38 papers selected by
Kıvanç Görgülü
Technical University of Munich

  1. Elife. 2022 Jul 11. pii: e73245. [Epub ahead of print]11
      Mitochondrial glutamate-oxaloacetate (GOT2) is part of the malate-aspartate shuttle (MAS), a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance induced by GOT2 KD, permitting sustained proliferation. Despite a strong in vitro inhibitory phenotype, loss of GOT2 had no effect on tumor growth in xenograft PDA or autochthonous mouse models. We show that cancer-associated fibroblasts (CAFs), a major component of the pancreatic tumor microenvironment (TME), release the redox active metabolite pyruvate, and culturing GOT2 KD cells in CAF conditioned media (CM) rescued proliferation in vitro. Furthermore, blocking pyruvate import or pyruvate-to-lactate reduction prevented rescue of GOT2 KD in vitro by exogenous pyruvate or CAF CM. However, these interventions failed to sensitize xenografts to GOT2 KD in vivo, demonstrating the remarkable plasticity and differential metabolism deployed by PDA cells in vitro and in vivo. This emphasizes how the environmental context of distinct pre-clinical models impacts both cell-intrinsic metabolic rewiring and metabolic crosstalk with the tumor microenvironment (TME).
    Keywords:  biochemistry; cancer biology; chemical biology; human; mouse
  2. J Natl Compr Canc Netw. 2022 07;pii: jnccn21524. [Epub ahead of print]20(7): 783-791.e1
    Trans-Atlantic Pancreatic Surgery (TAPS) Consortium
      BACKGROUND: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain.METHODS: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012-2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0-20 vs 21-40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1-4 vs 5-8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis.
    RESULTS: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score-matched. After matching, median OS was 26.2 months (95% CI, 24.0-38.4) with RT versus 32.8 months (95% CI, 25.3-42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92).
    CONCLUSIONS: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.
  3. J Clin Oncol. 2022 Jul 15. JCO2102514
      The management of pancreatic ductal adenocarcinoma (PDAC) has posed a considerable challenge for decades, with incidence and mortality rates almost mirroring each other. Despite this, a deeper understanding of the complex biology inherent to PDAC has provided a roadmap for a more precise approach to treatment. PDAC deficient in homologous recombination repair and mismatch repair is a subgroup that should be identified in the clinic for a targeted approach. In addition, KRAS wild-type PDAC, occurring in approximately 10% of patients, is enriched in highly actionable alterations including fusions, underscoring the importance of integrative germline and somatic sequencing. Comprehensive sequencing efforts over the past decade have documented genomic- and transcriptomic-based classifiers, with the latter emerging as two main subtypes: the classical and basal-like, which are now being evaluated in clinical trials. Together with promising, innovative strategies to target KRAS mutations and their pleotropic effects, a new era of precision medicine in PDAC is on the horizon.
  4. Nat Protoc. 2022 Jul 15.
      Here we provide a detailed tutorial on CRISPR in vivo screening. Using the mouse as the model organism, we introduce a range of CRISPR tools and applications, delineate general considerations for 'transplantation-based' or 'direct in vivo' screening design, and provide details on technical execution, sequencing readouts, computational analyses and data interpretation. In vivo screens face unique pitfalls and limitations, such as delivery issues or library bottlenecking, which must be counteracted to avoid screening failure or flawed conclusions. A broad variety of in vivo phenotypes can be interrogated such as organ development, hematopoietic lineage decision and evolutionary licensing in oncogenesis. We describe experimental strategies to address various biological questions and provide an outlook on emerging CRISPR applications, such as genetic interaction screening. These technological advances create potent new opportunities to dissect the molecular underpinnings of complex organismal phenotypes.
  5. Trends Cell Biol. 2022 Jul 12. pii: S0962-8924(22)00151-9. [Epub ahead of print]
      Autophagy is a multistage, intracellular process. Here, we highlight a recently identified autophagosomal components recycling (ACR) stage and the recycler complex (SNX4-SNX5-SNX17), which mediates recycling of autophagosomal outer membrane proteins on the autolysosome surface immediately following autophagosome-lysosome fusion. This discovery opens numerous research directions into the postfusion fate of autophagosomes.
    Keywords:  ATG9A; STX17; autophagosomal components recycling; autophagy; lysosome
  6. J Clin Oncol. 2022 Jul 15. JCO2102616
      The rising incidence and persistent dismal 5-year overall survival of pancreatic ductal adenocarcinoma (PDAC) highlight the need for new effective systemic therapies. Immunotherapy has shown significant benefits in solid organ tumors, but has thus far been disappointing in the treatment of PDAC. There have been several promising preclinical studies, but translation into the clinic has proved to be challenging. This is likely a result of PDAC's complex immunosuppressive tumor microenvironment that acts to insulate the tumor against an effective cytotoxic immune response. Here, we summarize the mechanisms of immunosuppression within the PDAC tumor microenvironment and provide an up-to-date review of completed and ongoing clinical trials using various immunotherapy strategies.
  7. Br J Cancer. 2022 Jul 15.
      BACKGROUND: Pharmacological inhibition of membrane transporters is expected to reduce the flow of solutes, unless flux is restored (i.e., autoregulated) through a compensatory increase in the transmembrane driving force. Drugs acting on monocarboxylate transporters (MCTs) have been developed to disrupt glycolytic metabolism, but autoregulation would render such interventions ineffective. We evaluated whether small-molecule MCT inhibitors reduce cellular H+/lactate production.METHODS: Cellular assays measured the relationship between MCT activity (expressed as membrane H+/lactate permeability; PHLac) and lactic acid production (inferred from H+ and lactate excretion; JHLac) in a panel of pancreatic ductal adenocarcinoma (PDAC) cells spanning a range of glycolytic phenotype.
    RESULTS: MCT activity did not correlate with lactic acid production, indicating that it is not set by membrane permeability properties. MCT inhibitors did not proportionately reduce JHLac because of a compensatory increase in the transmembrane [lactate] driving force. JHLac was largely insensitive to [lactate], therefore its cytoplasmic build-up upon MCT inhibition does not hinder glycolytic production. Extracellular acidity, an MCT inhibitor, reduced JHLac but this was via cytoplasmic acidification blocking glycolytic enzymes.
    CONCLUSIONS: We provide mathematically verified evidence that pharmacological and physiological modulators of MCTs cannot proportionately reduce lactic acid production because of the stabilising effect of autoregulation on overall flux.
  8. Clin Exp Metastasis. 2022 Jul 13.
      Anchorage-independent survival of cancer cells is associated with metastasis as it enables cells to travel to secondary target sites. Tissue integrity is generally maintained by detachment-induced cell death called 'anoikis', but cancer cells undergoing the multistep metastatic process show resistance to anoikis. Anoikis resistance enables these cells to survive through the extracellular matrix (ECM) deprived phase, which starts when cancer cells detach and move into the circulation till cells reach to the secondary target site. Comprehensive analysis of the molecular and functional biology of anoikis resistance in cancer cells will provide crucial details about cancer metastasis, enabling us to identify novel therapeutic targets against cancer cell dissemination and ultimately secondary tumor formation. This review broadly summarizes recent advances in the understanding of cellular and molecular events leading to anoikis and anoikis resistance. It further elaborates more about the signaling cross-talk in anoikis resistance and its regulation during metastasis.
    Keywords:  Anoikis; Apoptosis; Autophagy; Circulating tumor cells (CTCs); Epithelial-mesenchymal transition (EMT); Immune suppression; Intravasation; Metastasis
  9. Cancer Treat Res Commun. 2022 Jun 30. pii: S2468-2942(22)00090-9. [Epub ahead of print] 100600
      Evidence supports the antitumoral effects of physical activity, either in experimental animal models or humans. However, the biological mechanisms by which physical exercise modulates tumoral development are still unclear. An important feature of the tumor cells is the altered energy metabolism, often associated with definitions of tumor aggressiveness. Nevertheless, exercise can cause global metabolic changes in the body, as well as modulate tumor metabolism. Here we specifically discuss the metabolic changes found in tumors and how exercise can contribute to anti-tumoral effects by modulating the mitochondrial function, and tricarboxylic acid cycle-related metabolites of cancer cells. The effect of physical exercise on tumor metabolism is a new possibility for comprehension of cancer biology and developing therapies focused on tumor energy metabolism.
    Keywords:  Anti-tumoral; Cancer; Mitochondria; OXPHOS; TCA cycle
  10. J Clin Invest. 2022 Jul 15. pii: e161454. [Epub ahead of print]132(14):
      Kirsten rat sarcoma virus (KRAS) gene mutations are present in more than 90% of pancreatic ductal adenocarcinomas (PDACs). KRASG12D is the most frequent alteration, promoting preneoplastic lesions and associating with a more aggressive phenotype. These tumors possess increased intratumoral lymphatic networks and frequent lymph node (LN) metastases. In this issue of the JCI, Luo, Li, et al. explored the relationship between the presence of the KRASG12D mutation and lymphangiogenesis in PDAC. The authors used in vitro and in vivo models and an elegant mechanistic approach to describe an alternative pathway for lymphangiogenesis promotion. KRASG12D induced SUMOylation of heterogenous nuclear ribonucleoprotein A1 (hnRNPA1) via SAE1 and SUMO2 activation. SUMOylated hnRNPA1 was loaded into extracellular vesicles (EVs) and internalized by human endothelial lymphatic cells (HLEC). Further, SUMOylated hnRNPA1 promoted lymphangiogenesis and LN metastasis by stabilizing prospero homeodomain protein 1 (PROX1) mRNA. These data provide mechanistic insight into cancer lymphangiogenesis with the potential for developing biomarkers and RAS pathway therapeutics.
  11. Cell Metab. 2022 Jul 07. pii: S1550-4131(22)00228-5. [Epub ahead of print]
      The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and T cells, we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8+ T cell cytotoxicity, revealing an unexpected metabolic shunt in the TCA cycle. Metabolically fit cytotoxic T cells shunt succinate out of the TCA cycle to promote autocrine signaling via the succinate receptor (SUCNR1). Cytotoxic T cells are reliant on pyruvate carboxylase (PC) to replenish TCA cycle intermediates. By contrast, lactate reduces PC-mediated anaplerosis. The inhibition of pyruvate dehydrogenase (PDH) is sufficient to restore PC activity, succinate secretion, and the activation of SUCNR1. These studies identify PDH as a potential drug target to allow CD8+ T cells to retain cytotoxicity and overcome a lactate-enriched TME.
    Keywords:  T cells; cancer metabolism; lactate; pyruvate; succinate; tumor immunity
  12. Cell Metab. 2022 Jul 08. pii: S1550-4131(22)00230-3. [Epub ahead of print]
      Hepatocellular carcinoma (HCC) is a typically fatal malignancy exhibiting genetic heterogeneity and limited therapy responses. We demonstrate here that HCCs consistently repress urea cycle gene expression and thereby become auxotrophic for exogenous arginine. Surprisingly, arginine import is uniquely dependent on the cationic amino acid transporter SLC7A1, whose inhibition slows HCC cell growth in vitro and in vivo. Moreover, arginine deprivation engages an integrated stress response that promotes HCC cell-cycle arrest and quiescence, dependent on the general control nonderepressible 2 (GCN2) kinase. Inhibiting GCN2 in arginine-deprived HCC cells promotes a senescent phenotype instead, rendering these cells vulnerable to senolytic compounds. Preclinical models confirm that combined dietary arginine deprivation, GCN2 inhibition, and senotherapy promote HCC cell apoptosis and tumor regression. These data suggest novel strategies to treat human liver cancers through targeting SLC7A1 and/or a combination of arginine restriction, inhibition of GCN2, and senolytic agents.
    Keywords:  GCN2; arginine; hepatocellular carcinoma; senescence; urea cycle
  13. JAMA Oncol. 2022 Jul 14.
      Importance: National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear.Objective: To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC.
    Design, Setting, and Participants: This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021.
    Interventions: Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; bolus fluorouracil, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2 over 46 hours).
    Main Outcomes and Measures: Each treatment arm's 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection.
    Results: Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively.
    Conclusions and Relevance: This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting.
    Trial Registration: Identifier: NCT02839343.
  14. Gut. 2022 Jul 11. pii: gutjnl-2022-327953. [Epub ahead of print]
  15. Nucleic Acids Res. 2022 Jul 13. pii: gkac584. [Epub ahead of print]
      Autophagy is a catabolic pathway that maintains cellular homeostasis under various stress conditions, including conditions of nutrient deprivation. To elevate autophagic flux to a sufficient level under stress conditions, transcriptional activation of autophagy genes occurs to replenish autophagy components. Thus, the transcriptional and epigenetic control of the genes regulating autophagy is essential for cellular homeostasis. Here, we applied integrated transcriptomic and epigenomic profiling to reveal the roles of plant homeodomain finger protein 20 (PHF20), which is an epigenetic reader possessing methyl binding activity, in controlling the expression of autophagy genes. Phf20 deficiency led to impaired autophagic flux and autophagy gene expression under glucose starvation. Interestingly, the genome-wide characterization of chromatin states by Assay for Transposase-Accessible Chromatin (ATAC)-sequencing revealed that the PHF20-dependent chromatin remodelling occurs in enhancers that are co-occupied by dimethylated lysine 36 on histone H3 (H3K36me2). Importantly, the recognition of H3K36me2 by PHF20 was found to be highly correlated with increased levels of H3K4me1/2 at the enhancer regions. Collectively, these results indicate that PHF20 regulates autophagy genes through enhancer activation via H3K36me2 recognition as an epigenetic reader. Our findings emphasize the importance of nuclear events in the regulation of autophagy.
  16. Cancer Discov. 2022 Jul 15. OF1
      The m5c and f5c RNA modifications support mitochondrial mRNA translation promoting metastasis.
  17. Nature. 2022 Jul 13.
      The morphology and functionality of the epithelial lining differ along the intestinal tract, but tissue renewal at all sites is driven by stem cells at the base of crypts1-3. Whether stem cell numbers and behaviour vary at different sites is unknown. Here we show using intravital microscopy that, despite similarities in the number and distribution of proliferative cells with an Lgr5 signature in mice, small intestinal crypts contain twice as many effective stem cells as large intestinal crypts. We find that, although passively displaced by a conveyor-belt-like upward movement, small intestinal cells positioned away from the crypt base can function as long-term effective stem cells owing to Wnt-dependent retrograde cellular movement. By contrast, the near absence of retrograde movement in the large intestine restricts cell repositioning, leading to a reduction in effective stem cell number. Moreover, after suppression of the retrograde movement in the small intestine, the number of effective stem cells is reduced, and the rate of monoclonal conversion of crypts is accelerated. Together, these results show that the number of effective stem cells is determined by active retrograde movement, revealing a new channel of stem cell regulation that can be experimentally and pharmacologically manipulated.
  18. Tumori. 2022 Jul 10. 3008916221110265
      BACKGROUND: Treatments for patients suffering from pancreatic cancer with oligo-hepatic metastasis have always been a cause of certain controversy. Herein, we reported 15 pancreatic cancer patients with oligo-hepatic metastasis who accepted sequential therapy of chemotherapy, radiofrequency ablation (RFA), and radical resection of the primary tumor.METHODS: A total of 87 pancreatic cancer patients with synchronous oligo-metastatic hepatic lesions who received treatments in the 2nd Affiliated Hospital of Zhejiang University between January 2017 and July 2020 were enrolled. The chemotherapy regimens included modified folfirinox (54/87) and gemcitabine plus nab-paclitaxel (33/87). Test of blood tumor markers and contrast-enhanced computed tomography (CT) or magnetic resonance (MR) scan was performed at diagnosis and after eight weeks of chemotherapy.
    RESULTS: Thirty-five patients received just chemotherapy because of poor reaction to the first round of chemotherapy(Overall survival (OS), 6.47±1.80 months); 15 patients reassessed as stable disease (SD)/partial response (PR) continued chemotherapy (OS, 10.35±3.15); nine patients reassessed as progressive disease (PD) after RFA and continued chemotherapy (OS, 10.90±2.60). The primary tumors in 13 patients were unresectable after chemotherapy and RFA (OS, 12.92±2.47), while 15 patients completed the sequential therapy of chemotherapy, radio-frequency ablation, and radical resection (OS, 16.76±6.55).
    CONCLUSIONS: Sequential chemotherapy and RFA is a good treatment strategy to select the best candidates for surgical treatment among patients with pancreatic cancer with oligo-hepatic metastasis.
    Keywords:  Pancreatic cancer; RFA; oligo-hepatic metastasis; radical resection; sequential therapy
  19. Cell. 2022 Jul 08. pii: S0092-8674(22)00787-5. [Epub ahead of print]
      Cancer vaccines aim to direct the immune system to eradicate cancer cells. Here we review the essential immunologic concepts underpinning natural immunity and highlight the multiple unique challenges faced by vaccines targeting cancer. Recent technological advances in mass spectrometry, neoantigen prediction, genetically and pharmacologically engineered mouse models, and single-cell omics have revealed new biology, which can help to bridge this divide. We particularly focus on translationally relevant aspects, such as antigen selection and delivery and the monitoring of human post-vaccination responses, and encourage more aggressive exploration of novel approaches.
  20. Nature. 2022 Jul 13.
      Mechanistic target of rapamycin complex 1 (mTORC1) controls growth by regulating anabolic and catabolic processes in response to environmental cues, including nutrients1,2. Amino acids signal to mTORC1 through the Rag GTPases, which are regulated by several protein complexes, including GATOR1 and GATOR2. GATOR2, which has five components (WDR24, MIOS, WDR59, SEH1L and SEC13), is required for amino acids to activate mTORC1 and interacts with the leucine and arginine sensors SESN2 and CASTOR1, respectively3-5. Despite this central role in nutrient sensing, GATOR2 remains mysterious as its subunit stoichiometry, biochemical function and structure are unknown. Here we used cryo-electron microscopy to determine the three-dimensional structure of the human GATOR2 complex. We found that GATOR2 adopts a large (1.1 MDa), two-fold symmetric, cage-like architecture, supported by an octagonal scaffold and decorated with eight pairs of WD40 β-propellers. The scaffold contains two WDR24, four MIOS and two WDR59 subunits circularized via two distinct types of junction involving non-catalytic RING domains and α-solenoids. Integration of SEH1L and SEC13 into the scaffold through β-propeller blade donation stabilizes the GATOR2 complex and reveals an evolutionary relationship to the nuclear pore and membrane-coating complexes6. The scaffold orients the WD40 β-propeller dimers, which mediate interactions with SESN2, CASTOR1 and GATOR1. Our work reveals the structure of an essential component of the nutrient-sensing machinery and provides a foundation for understanding the function of GATOR2 within the mTORC1 pathway.
  21. Trends Cancer. 2022 Jul 07. pii: S2405-8033(22)00135-2. [Epub ahead of print]
      Cancer is an age-related disease, as incidence and mortality for most types of cancer increase with age. However, how molecular alterations in tumors differ among patients of different ages remains poorly understood. Recent studies have shed light on the age-associated molecular landscapes in cancer. Here, we summarize the main findings of these current studies, highlighting major differences in the genomic, transcriptomic, epigenetic, and immunological landscapes between cancer in younger and older patients. Importantly, some cancer driver genes are mutated more frequently in younger or older patients. We discuss the potential roles of aging-related processes in shaping these age-related differences in cancer. We further emphasize the remaining unsolved questions that could provide important insights that will have implications in personalized medicine.
    Keywords:  aging; cancer genomics; cancer immune landscape; carcinoma; microenvironment
  22. Int J Cancer. 2022 Jul 13.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by high heterogeneity, and the postoperative prognosis of different patients often varies greatly. Therefore, the classification of pancreatic cancer patients and precise treatment becomes particularly important. In this study, 1 H NMR spectroscopy was used to analyze the 76 PDAC serum samples and identify the potential metabolic subtypes. The metabolic characteristics of each metabolic subtype were screened out and the relationship between metabolic subtype and the long-term prognosis was further identified. The clinical stages of PDAC did not show the metabolic differences at the serum metabolomic level. And three metabolic subtypes, basic, choline-like and amino acid-enriched types, were defined by the HCA of the serum metabolites and the disturbed metabolic pathways. The characteristic metabolites of each PDAC subtype were identified, and the metabolite model was established to distinguish the PDAC patients in the different subtypes. Among the three metabolic subtypes, choline-like type displayed better long-term prognosis compared with the other two types of patients. Metabolic subtypes are of clinical importance and are closer to expressing the heterogeneity in the actual life activities of pancreatic cancer than molecular typing. The excavation of metabolic subtypes based on this will be more in line with clinical reality and more promising to guide clinical precision individualization treatment.
    Keywords:  metabolic subtype; pancreatic cancer; prognosis; survival
  23. Autophagy. 2022 Jul 09.
      The conjugation of Atg8-family proteins with phospholipids on the double-membrane phagophore is one of the hallmarks of macroautopahgy/autophagy. However, in the past decades, Atg8-family proteins are also found on single-membrane structures, including the phagosome, endosome and lysosome. While the physiological importance of the non-canonical Atg8-family protein conjugation has been demonstrated, the mechanism of this process and the underlying regulation are still not very clear. In a recent paper, Hooper et al. found that during LC3-associated phagocytosis, reactive oxygen species are required for V-ATPase assembly, which is essential for the subsequent LC3 conjugation to the phagosome. Enhanced V-ATPase assembly and the direct engagement of ATG16L1 are also observed in a wide range of non-canonical Atg8-family protein conjugation processes, defining the V-ATPase and ATG16L1 as taking part in a common mechanism.
    Keywords:  ATG16L1; Atg8 conjugation; LAP; ROS; V-ATPase; non-canonical autophagy
  24. Elife. 2022 Jul 15. pii: e80890. [Epub ahead of print]11
      The diet and age of mice can modulate how different genetic variants impact body weight, demonstrating the need to take context into account when performing genetic studies.
    Keywords:  diversity outbred mice; gene-environment interaction; genetics; genomics; heritability; longitudinal; mixed models; mouse; quantitative trait locus
  25. Eur J Cancer. 2022 Jul 07. pii: S0959-8049(22)00350-1. [Epub ahead of print]172 300-310
      BACKGROUND: Cyclic fasting or calorie-restricted, low-carbohydrate, low-protein diets, collectively referred to as fasting-mimicking diets (FMDs), demonstrated additive or synergistic antitumour effects when combined with chemotherapy, targeted therapies, or immunotherapy in several preclinical in vivo models, including murine models of breast cancer, lung cancer, and colorectal cancer. However, no data on the antitumour efficacy of cyclic FMD in patients with cancer have been published so far. Here, we aim at reporting on patients with advanced cancer achieving complete and long-lasting tumour remissions with cyclic FMD in combination with standard anticancer therapies in the context of the phase Ib NCT03340935 trial.PATIENTS AND METHODS: The NCT03340935 trial enrolled 101 patients with different tumour types, and it showed that a severely calorie-restricted FMD regimen is safe and feasible in patients with cancer receiving concomitant standard-of-care antineoplastic therapies. In addition, cyclic FMD resulted in positive metabolic and immunologic modifications, thus recapitulating the biological effects that in preclinical models were found to mediate the antitumour effects of fasting/FMD.
    RESULTS: Of the 101 patients enrolled in the NCT03340935 trial, we identified five patients with advanced, poor prognosis solid neoplasms (n = 1: extensive stage small cell lung cancer; n = 1: metastatic pancreatic adenocarcinoma; n = 1: metastatic colorectal cancer; n = 2: metastatic triple-negative breast cancer), who achieved complete and long-lasting tumour responses when treated with a combination of cyclic FMD and standard systemic treatments in the context of the NCT03340935 trial.
    CONCLUSION: These excellent responses prompt the initiation of clinical trials to investigate cyclic FMD in combination with standard antitumour therapies in specific clinical contexts.
    Keywords:  Advanced solid neoplasms; Anticancer treatments; Complete tumour response; Fasting-mimicking diet; Long-term patient survival
  26. Nat Cancer. 2022 Jul 14.
      Complex genomic rearrangements (CGRs) are common in cancer and are known to form via two aberrant cellular structures-micronuclei and chromatin bridges. However, which of these mechanisms is more relevant to CGR formation in cancer and whether there are other undiscovered mechanisms remain unknown. Here we developed a computational algorithm, 'Starfish', to analyze 2,014 CGRs from 2,428 whole-genome-sequenced (WGS) tumors and discovered six CGR signatures based on their copy number and breakpoint patterns. Extensive benchmarking showed that our CGR signatures are highly accurate and biologically meaningful. Three signatures can be attributed to known biological processes-micronuclei- and chromatin-bridge-induced chromothripsis and circular extrachromosomal DNA. Over half of the CGRs belong to the remaining three signatures, not reported previously. A unique signature, which we named 'hourglass chromothripsis', with localized breakpoints and a low amount of DNA loss, is abundant in prostate cancer. Hourglass chromothripsis is associated with mutant SPOP, which may induce genome instability.
  27. Cell. 2022 Jul 01. pii: S0092-8674(22)00721-8. [Epub ahead of print]
      Cellular carbohydrates or glycans are critical mediators of biological function. Their remarkably diverse structures and varied activities present exciting opportunities for understanding many areas of biology. In this primer, we discuss key methods and recent breakthrough technologies for identifying, monitoring, and manipulating glycans in mammalian systems.
    Keywords:  carbohydrates; glycans; glycobiology; mammalian biology
  28. Nutrition. 2022 Apr 30. pii: S0899-9007(22)00124-1. [Epub ahead of print]102 111711
      OBJECTIVES: Cancer cachexia is a systemic paraneoplastic phenomenon involving multiple organs, including the liver. Total bilirubin (TBIL) is an easily obtained blood biomarker that reflects liver homeostasis. The aim of this study was to evaluate the prognostic value of serum TBIL in patients with cancer cachexia.METHODS: This study included 2282 patients from a multicenter research database who were diagnosed with cancer cachexia between June 2012 and December 2019. The hazard ratio (HR) for all-cause mortality was analyzed using Cox proportional hazards regression models. The association of serum TBIL with all-cause mortality was modeled with restricted cubic splines. The optimal cutoff value for TBIL was calculated with maximally selected rank statistics.
    RESULTS: Of the participants, there were 1327 (58.2%) men and 955 (41.8%) women. The mean patient age was 60.4 ± 1.5 y. The 12-mo all-cause mortality rate for patients with cancer cachexia was 29.5% (95% confidence interval [CI], 27.6%-31.3%), resulting in a rate of 209.58 events per 1000 patient-years. An inverted L-shaped association between TBIL and all-cause mortality was observed. The cutoff point for TBIL for the prediction of the time to mortality was <21.7 µmol/L. A high TBIL level but not the direct bilirubin or indirect bilirubin level was identified as an independent prognostic factor (HR, 1.60; 95% CI, 1.32-1.93). For patients with digestive system tumors, a high serum TBIL level (≥21.7 µmol/L) was significantly associated with mortality.
    CONCLUSION: High TBIL levels are associated with increased all-cause mortality in patients and might be a promising prognostic indicator in patients with cancer cachexia.
    Keywords:  Cancer cachexia; Liver function; Prognostic; Total bilirubin
  29. Mol Ther. 2022 Jul 14. pii: S1525-0016(22)00429-4. [Epub ahead of print]
      Simultaneous inhibition of interleukin-6 (IL-6) and interleukin-8 (IL-8) signaling diminishes cancer cell migration, and combination therapy has recently been shown to synergistically reduce metastatic burden in a preclinical model of triple negative breast cancer. Here, we have engineered two novel bispecific antibodies that target the IL-6 and IL-8 receptors to concurrently block the signaling activity of both ligands. We demonstrate that a first-in-class bispecific antibody design has promising therapeutic potential, with enhanced selectivity and potency compared to monoclonal antibody and small molecule drug combinations in both cellular and animal models of metastatic triple negative breast cancer. Mechanistic characterization revealed that our engineered bispecific antibodies have no impact on cell viability, but profoundly reduce the migratory potential of cancer cells; hence they constitute a true anti-metastatic treatment. Moreover, we demonstrate that our antibodies can be readily combined with standard of care anti-proliferative drugs to develop effective anti-cancer regimens. Collectively, our work establishes an innovative metastasis-focused direction for cancer drug development.
    Keywords:  Antibody; Breast cancer; Cell migration; Interleukins; Metastasis
  30. Mol Oncol. 2022 Jul 10.
      Resistance to gemcitabine is the main challenge of chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Hence, development of a response signature to gemcitabine is essential for precision therapy of PDAC. However, existing quantitative signatures of gemcitabine are susceptible to batch effects and variations in sequencing platforms. Therefore, based on within-sample relative expression ordering of pairwise genes, we developed a transcriptome-based gemcitabine signature consisting of 28 gene pairs (28-GPS) that could predict response to gemcitabine for PDAC at the individual level. The 28-GPS was superior to previous quantitative signatures in terms of classification accuracy and prognostic performance. Resistant samples classified by 28-GPS showed poorer overall survival, higher genomic instability, lower immune infiltration, higher metabolic level, and higher-fidelity DNA damage repair compared to sensitive samples. Additionally, we found that gemcitabine combined with phosphoinositide 3-kinase (PI3K) inhibitor may be an alternative treatment strategy for PDAC. Single-cell analysis revealed that cancer cells in the same PDAC sample showed both the characteristics of sensitivity and resistance to gemcitabine, and the activation of the TGFβ signaling pathway could promote progression of PDAC. In brief, 28-GPS could robustly determine whether PDAC is resistant or sensitive to gemcitabine, and may be an auxiliary tool for clinical treatment.
    Keywords:  Drug response signature; Gemcitabine; Immunity; Pancreatic ductal adenocarcinoma; Single cell
  31. Theranostics. 2022 ;12(11): 4980-4992
      Rationale: The biology of the pancreatic ductal adenocarcinoma (PDAC) is heterogenous, but how heterogenity of the tumor microenvironment contributes to disparate patient outcomes remains essentially unstudied. Methods: A strategy employing multiplex digital spatial profiling (mplxDSP) technology was employed to evaluate the nature and dynamics of microenvironment components including cancer associated fibroblasts (CAFs) and infiltrating immune cells at the single-cell level based upon their spatial relationship within the tumor. Results: We report that myofibroblasts directly adjacent to PDAC tumors comparatively overexpress genes (BATF3, IL12B, ITGB8, CD4 and IFNAR1), constructing pathways prone to stimulating an adaptive immune response. Markers of innate immune cells (Natural Killer cells, Dendritic Cells and macrophages) are predominant in CD45+ cells immediately adjacent to PDAC tumor, however, the checkpoint protein CTLA4 is also overwhelmingly expressed, fostering tolerance. Finaly, mRNA profiling of adjacent CAFs identified clusters of genes that correlate with survival. Conclusion: CAFs and leukocytes in close proximity to PDAC significantly differ from those remote from the tumor, providing insight into microenvironment influence on immune tolerance mediated through relative populations of leukocytes and subsets of CAFs and monocytes. mRNA expression profiling of CAFs adjacent to PDAC cells may hold promise for prognostication.
    Keywords:  digital spatial profiling; immune tolerance; pancreas; stromal interaction; tumor microenvironment
  32. Cell. 2022 Jul 11. pii: S0092-8674(22)00781-4. [Epub ahead of print]
      Metabolic anomalies contribute to tissue dysfunction. Current metabolism research spans from organelles to populations, and new technologies can accommodate investigation across these scales. Here, we review recent advancements in metabolic analysis, including small-scale metabolomics techniques amenable to organelles and rare cell types, functional screening to explore how cells respond to metabolic stress, and imaging approaches to non-invasively assess metabolic perturbations in diseases. We discuss how metabolomics provides an informative phenotypic dimension that complements genomic analysis in Mendelian and non-Mendelian disorders. We also outline pressing challenges and how addressing them may further clarify the biochemical basis of human disease.
    Keywords:  genomics; magnetic resonance; metabolism; metabolomics; molecular imaging; positron emission tomography; stable isotopes
  33. Front Aging. 2022 ;3 828239
      Complexity is a fundamental feature of biological systems. Omics techniques like lipidomics can simultaneously quantify many thousands of molecules, thereby directly capturing the underlying biological complexity. However, this approach transfers the original biological complexity to the resulting datasets, posing challenges in data reduction and analysis. Aging is a prime example of a process that exhibits complex behaviour across multiple scales of biological organisation. The aging process is characterised by slow, cumulative and detrimental changes that are driven by intrinsic biological stochasticity and mediated through non-linear interactions and feedback within and between these levels of organization (ranging from metabolites, macromolecules, organelles and cells to tissue and organs). Only collectively and over long timeframes do these changes manifest as the exponential increases in morbidity and mortality that define biological aging, making aging a problem more difficult to study than the aetiologies of specific diseases. But aging's time dependence can also be exploited to extract key insights into its underlying biology. Here we explore this idea by using data on changes in lipid composition across the lifespan of an organism to construct and test a LipidClock to predict biological age in the nematode Caenorhabdits elegans. The LipidClock consist of a feature transformation via Principal Component Analysis followed by Elastic Net regression and yields and Mean Absolute Error of 1.45 days for wild type animals and 4.13 days when applied to mutant strains with lifespans that are substantially different from that of wild type. Gompertz aging rates predicted by the LipidClock can be used to simulate survival curves that are in agreement with those from lifespan experiments.
    Keywords:  Caenorhabditis elegans; aging; aging clock; biomarker; lipidomics; lipids; machine learning
  34. Nat Immunol. 2022 Jul 11.
      Lymph nodes (LNs) comprise two main structural elements: fibroblastic reticular cells that form dedicated niches for immune cell interaction and capsular fibroblasts that build a shell around the organ. Immunological challenge causes LNs to increase more than tenfold in size within a few days. Here, we characterized the biomechanics of LN swelling on the cellular and organ scale. We identified lymphocyte trapping by influx and proliferation as drivers of an outward pressure force, causing fibroblastic reticular cells of the T-zone (TRCs) and their associated conduits to stretch. After an initial phase of relaxation, TRCs sensed the resulting strain through cell matrix adhesions, which coordinated local growth and remodeling of the stromal network. While the expanded TRC network readopted its typical configuration, a massive fibrotic reaction of the organ capsule set in and countered further organ expansion. Thus, different fibroblast populations mechanically control LN swelling in a multitier fashion.
  35. Semin Cancer Biol. 2022 Jul 06. pii: S1044-579X(22)00162-6. [Epub ahead of print]
      Tumors have long been known to rewire their metabolism to endorse their proliferation, growth, survival, and invasiveness. One of the common characteristics of these alterations is the enhanced glucose uptake and its subsequent transformation into lactic acid by means of glycolysis, regardless the availability of oxygen or the mitochondria effectiveness. This phenomenon is called the "Warburg effect", which has turned into a century of age now, since its first disclosure by German physiologist Otto Heinrich Warburg. Since then, this peculiar metabolic switch in tumors has been addressed by extensive studies covering several areas of research. In this historical perspective, we aim at illustrating the evolution of these studies over time and their implication in various fields of science.
    Keywords:  Aerobic glycolysis; Historical perspective; Reverse Warburg effect; Tumor metabolism; Warburg effect
  36. J Clin Invest. 2022 Jul 15. pii: e158448. [Epub ahead of print]132(14):
      Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging - and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.
  37. Mol Biol Cell. 2022 Jul 13. mbcE22020070
      Cancer cells are known to have larger nucleoli, consistent with their higher transcriptional and translational demands. Meanwhile, on stiff extracellular matrix, normal epithelial cells can exhibit genomic and proteomic mechano-activation towards tumorigenic transformations, such as epithelial-mesenchymal transition and enhanced migration. However, while nucleolar bodies regulate the protein synthesis required for mechano-sensation, it remains unknown whether mechanical and spatial extracellular cues can in turn alter nucleoli. Here, we culture mammary epithelial cell sheets on matrices of varying stiffness and show that cancer cells have more nucleoli, with nucleoli occupying larger areas compared to normal cells. By contrast, within normal epithelial sheets, stiffer matrices and leader positioning of cells induces larger nucleolar areas and more nucleolar bodies over time. The observed leader-follower nucleolar differences stem from distinct rates of cell cycle progression. In the nucleoplasm, leader cells on stiffer matrices exhibit higher heterochromatin marker expression and DNA compaction around nucleolar bodies. Overall, our findings advance the emerging framework of cellular mechanobiology in which mechanical cues from the extracellular matrix transmit into the nucleoplasm to alter nucleolar composition, potentially resulting in mechanosensitive ribosomal biogenesis. Ultimately, this proposed mechanosensitivity of nucleoli and associated protein synthesis could have wide implications in disease, development, and regeneration.
  38. J Clin Invest. 2022 Jul 15. pii: e157410. [Epub ahead of print]132(14):
      The metabolic dependencies of cancer cells have substantial potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is identified as a urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high CR levels in patients with cancer as well as their implications for the treatment of these aggressive cancers remain unclear. By integrating multiomics data on lung and liver cancer, we have shown that CR is a cancer cell-derived metabolite. Global metabolomics and gene expression analysis of human tumors and matched liquid biopsies, together with functional studies, revealed that dysregulation of the mitochondrial urea cycle and a nucleotide imbalance were associated with high CR levels and indicators of a poor prognosis. This metabolic phenotype was associated with reduced immune infiltration and supported rapid cancer cell proliferation that drove aggressive tumor growth. CRhi cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of CR not only as a poor-prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve survival for patients with cancer.
    Keywords:  Cancer; Lung cancer; Oncology