bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022–09–04
37 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Mitochondria in cancer: clean windmills or stressed tinkerers?
  2. Senescence and cancer - role and therapeutic opportunities.
  3. In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.
  4. Sublethal cytochrome c release generates drug-tolerant persister cells.
  5. Mitochondrial DNA is a major source of driver mutations in cancer.
  6. Non-degradable autophagic vacuoles are indispensable for cell competition.
  7. Extracellular vesicles and particles impact the systemic landscape of cancer.
  8. Lipid metabolic reprogramming extends beyond histological tumor demarcations in operable human pancreatic cancer.
  9. Identification of two pathways mediating protein targeting from ER to lipid droplets.
  10. Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.
  11. Phosphorylation of FAM134C by CK2 controls starvation-induced ER-phagy.
  12. Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial.
  13. The Interplay between Autophagy and Regulated Necrosis.
  14. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.
  15. Gut bacterial nutrient preferences quantified in vivo.
  16. Genome-wide in vivo screen of circulating tumor cells identifies SLIT2 as a regulator of metastasis.
  17. AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene.
  18. Life in lockdown: Orchestrating endoplasmic reticulum and lysosome homeostasis for quiescent cells.
  19. The histone methyltransferase SETD2 negatively regulates cell size.
  20. SQSTM1/p62 promotes miR-198 loading into extracellular vesicles and its autophagy-related secretion.
  21. The endoplasmic reticulum contributes to lysosomal tubulation/sorting driven by LRRK2.
  22. Nucleolar targeting in an early-branching eukaryote suggests a general mechanism for ribosome protein sorting.
  23. Quality control mechanisms that protect nuclear envelope identity and function.
  24. Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors in Oncology Clinical Trials: A review.
  25. Involvement of acetylation of ATG4B in controlling autophagy induction.
  26. Operation of a TCA cycle subnetwork in the mammalian nucleus.
  27. Assessment of MRI to estimate metastatic dissemination risk and prometastatic effects of chemotherapy.
  28. Nuclear fascin regulates cancer cell survival.
  29. Clinical application of advanced multi-omics tumor profiling: Shaping precision oncology of the future.
  30. FOLFIRINOX or gemcitabine/nab-paclitaxel in advanced pancreatic adenocarcinoma - A novel validated prognostic score to facilitate treatment decision-making in real-world.
  31. Resolving the spatial heterogeneity of cancer in 3D.
  32. The role of somatosensory innervation of adipose tissues.
  33. Almost half of cancer deaths are preventable.
  34. Ubiquitination of phosphatidylethanolamine in organellar membranes.
  35. Imaging and analysis for simultaneous tracking of fluorescent biosensors in barcoded cells.
  36. Simultaneous metabolite MALDI-MSI, whole exome and transcriptome analysis from formalin-fixed paraffin-embedded tissue sections.
  37. The improving benefit-risk balance of phase I cancer trials.
  1. Trends Cell Biol. 2022 Aug 18. pii: S0962-8924(22)00191-X. [Epub ahead of print]
    Mitochondria in cancer: clean windmills or stressed tinkerers?
    Dario C Altieri.
      There is now a consensus that mitochondria are important tumor drivers, sophisticated biological machines that can engender a panoply of key disease traits. How this happens, however, is still mostly elusive. The opinion presented here is that what cancer exploits are not the normal mitochondria of oxygenated and nutrient-replete tissues, but the unfit, damaged, and dysfunctional organelles generated by the hostile environment of tumor growth. These 'ghost' mitochondria survive quality control and thwart cell death to relay multiple comprehensive 'danger signals' of metabolic starvation, cellular stress, and reprogrammed gene expression. The result is a new, treacherous cellular phenotype, proliferatively quiescent but highly motile, that enables tumor cell escape from a threatening environment and colonization of distant, more favorable sites (metastasis).
    Keywords:  Mic60; metabolism; metastasis; mitochondria; tumor plasticity
    DOI:  https://doi.org/10.1016/j.tcb.2022.08.001
  2. Nat Rev Clin Oncol. 2022 Aug 31.
    Senescence and cancer - role and therapeutic opportunities.
    Clemens A Schmitt, Boshi Wang, Marco Demaria.
      Cellular senescence is a state of stable, terminal cell cycle arrest associated with various macromolecular changes and a hypersecretory, pro-inflammatory phenotype. Entry of cells into senescence can act as a barrier to tumorigenesis and, thus, could in principle constitute a desired outcome for any anticancer therapy. Paradoxically, studies published in the past decade have demonstrated that, in certain conditions and contexts, malignant and non-malignant cells with lastingly persistent senescence can acquire pro-tumorigenic properties. In this Review, we first discuss the major mechanisms involved in the antitumorigenic functions of senescent cells and then consider the cell-intrinsic and cell-extrinsic factors that participate in their switch towards a tumour-promoting role, providing an overview of major translational and emerging clinical findings. Finally, we comprehensively describe various senolytic and senomorphic therapies and their potential to benefit patients with cancer.
    DOI:  https://doi.org/10.1038/s41571-022-00668-4
  3. Sci Adv. 2022 Sep 02. 8(35): eabn9550
    In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.
    Panayotis Pachnis, Zheng Wu, Brandon Faubert, Alpaslan Tasdogan, Wen Gu, Spencer Shelton, Ashley Solmonson, Aparna D Rao, Akash K Kaushik, Thomas J Rogers, Jessalyn M Ubellacker, Collette A LaVigne, Chendong Yang, Bookyung Ko, Vijayashree Ramesh, Jessica Sudderth, Lauren G Zacharias, Misty S Martin-Sandoval, Duyen Do, Thomas P Mathews, Zhiyu Zhao, Prashant Mishra, Sean J Morrison, Ralph J DeBerardinis.
      In mice and humans with cancer, intravenous 13C-glucose infusion results in 13C labeling of tumor tricarboxylic acid (TCA) cycle intermediates, indicating that pyruvate oxidation in the TCA cycle occurs in tumors. The TCA cycle is usually coupled to the electron transport chain (ETC) because NADH generated by the cycle is reoxidized to NAD+ by the ETC. However, 13C labeling does not directly report ETC activity, and other pathways can oxidize NADH, so the ETC's role in these labeling patterns is unverified. We examined the impact of the ETC complex I inhibitor IACS-010759 on tumor 13C labeling. IACS-010759 suppresses TCA cycle labeling from glucose or lactate and increases labeling from glutamine. Cancer cells expressing yeast NADH dehydrogenase-1, which recycles NADH to NAD+ independently of complex I, display normalized labeling when complex I is inhibited, indicating that cancer cell ETC activity regulates TCA cycle metabolism and 13C labeling from multiple nutrients.
    DOI:  https://doi.org/10.1126/sciadv.abn9550
  4. Cell. 2022 Sep 01. pii: S0092-8674(22)00978-3. [Epub ahead of print]185(18): 3356-3374.e22
    Sublethal cytochrome c release generates drug-tolerant persister cells.
    Halime Kalkavan, Mark J Chen, Jeremy C Crawford, Giovanni Quarato, Patrick Fitzgerald, Stephen W G Tait, Colin R Goding, Douglas R Green.
      Drug-tolerant persister cells (persisters) evade apoptosis upon targeted and conventional cancer therapies and represent a major non-genetic barrier to effective cancer treatment. Here, we show that cells that survive treatment with pro-apoptotic BH3 mimetics display a persister phenotype that includes colonization and metastasis in vivo and increased sensitivity toward ferroptosis by GPX4 inhibition. We found that sublethal mitochondrial outer membrane permeabilization (MOMP) and holocytochrome c release are key requirements for the generation of the persister phenotype. The generation of persisters is independent of apoptosome formation and caspase activation, but instead, cytosolic cytochrome c induces the activation of heme-regulated inhibitor (HRI) kinase and engagement of the integrated stress response (ISR) with the consequent synthesis of ATF4, all of which are required for the persister phenotype. Our results reveal that sublethal cytochrome c release couples sublethal MOMP to caspase-independent initiation of an ATF4-dependent, drug-tolerant persister phenotype.
    Keywords:  ATF4; Bcl-2 family; GPX4; HRI; ferroptosis; persister integrated stress response
    DOI:  https://doi.org/10.1016/j.cell.2022.07.025
  5. Trends Cancer. 2022 Aug 27. pii: S2405-8033(22)00172-8. [Epub ahead of print]
    Mitochondrial DNA is a major source of driver mutations in cancer.
    Minsoo Kim, Mahnoor Mahmood, Ed Reznik, Payam A Gammage.
      Mitochondrial DNA (mtDNA) mutations are among the most common genetic events in all tumors and directly impact metabolic homeostasis. Despite the central role mitochondria play in energy metabolism and cellular physiology, the role of mutations in the mitochondrial genomes of tumors has been contentious. Until recently, genomic and functional studies of mtDNA variants were impeded by a lack of adequate tumor mtDNA sequencing data and available methods for mitochondrial genome engineering. These barriers and a conceptual fog surrounding the functional impact of mtDNA mutations in tumors have begun to lift, revealing a path to understanding the role of this essential metabolic genome in cancer initiation and progression. Here we discuss the history, recent developments, and challenges that remain for mitochondrial oncogenetics as the impact of a major new class of cancer-associated mutations is unveiled.
    Keywords:  cancer; genome editing; mitochondrial DNA; mutation selection
    DOI:  https://doi.org/10.1016/j.trecan.2022.08.001
  6. Cell Rep. 2022 Aug 30. pii: S2211-1247(22)01112-3. [Epub ahead of print]40(9): 111292
    Non-degradable autophagic vacuoles are indispensable for cell competition.
    Eilma Akter, Yukihiro Tasaki, Yusuke Mori, Kazuki Nakai, Kazuki Hachiya, Hancheng Lin, Masamitsu Konno, Tomoko Kamasaki, Kenji Tanabe, Yumi Umeda, Shotaro Yamano, Yasuyuki Fujita, Shunsuke Kon.
      Cell competition is a process by which unwanted cells are eliminated from tissues. Apical extrusion is one mode whereby normal epithelial cells remove transformed cells, but it remains unclear how this process is mechanically effected. In this study, we show that autophagic and endocytic fluxes are attenuated in RasV12-transformed cells surrounded by normal cells due to lysosomal dysfunction, and that chemical manipulation of lysosomal activity compromises apical extrusion. We further find that RasV12 cells deficient in autophagy initiation machinery are resistant to elimination pressure exerted by normal cells, suggesting that non-degradable autophagic vacuoles are required for cell competition. Moreover, in vivo analysis revealed that autophagy-ablated RasV12 cells are less readily eliminated by cell competition, and remaining transformed cells destroy ductal integrity, leading to chronic pancreatitis. Collectively, our findings illuminate a positive role for autophagy in cell competition and reveal a homeostasis-preserving function of autophagy upon emergence of transformed cells.
    Keywords:  CP: Cell biology; autophagic flux; cell competition; lysosomal dysfunction; non-degradable autophagic vacuoles; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.celrep.2022.111292
  7. EMBO J. 2022 Sep 02. e109288
    Extracellular vesicles and particles impact the systemic landscape of cancer.
    Serena Lucotti, Candia M Kenific, Haiying Zhang, David Lyden.
      Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
    Keywords:  biomarkers; cancer; extracellular vesicles and particles; metastasis; therapeutic deliverables
    DOI:  https://doi.org/10.15252/embj.2021109288
  8. Cancer Res. 2022 Sep 02. pii: CAN-22-0396. [Epub ahead of print]
    Lipid metabolic reprogramming extends beyond histological tumor demarcations in operable human pancreatic cancer.
    Juho Pirhonen, Ábel Szkalisity, Jaana K Hagström, Yonghyo Kim, Ede Migh, Mária Kovács, Maarit Hölttä, Johan Peränen, Hanna Seppänen, Caj Haglund, Jeovanis Gil, Melinda Rezeli, Johan Malm, Peter Horvath, Gyorgy Marko-Varga, Pauli Puolakkainen, Elina Ikonen.
      Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies and potentially curable only with radical surgical resection at early stages. The tumor microenvironment has been shown to be central to the development and progression of PDAC. A better understanding of how early human PDAC metabolically communicates with its environment and differs from healthy pancreas could help improve PDAC diagnosis and treatment. Here we performed deep proteomic analyses from diagnostic specimens of operable, treatment-naïve PDAC patients (n=14), isolating four tissue compartments by laser-capture microdissection: PDAC lesions, tumor-adjacent but morphologically benign exocrine glands, and connective tissues neighboring each of these compartments. Protein and pathway levels were compared between compartments and with control pancreatic proteomes. Selected targets were studied immunohistochemically in the 14 patients and in additional tumor microarrays, and lipid deposition was assessed by non-linear label-free imaging (n=16). Widespread downregulation of pancreatic secretory functions was observed, which was paralleled by high cholesterol biosynthetic activity without prominent lipid storage in the neoplastic cells. Stromal compartments harbored ample blood apolipoproteins, indicating the abundant microvasculature at the time of tumor removal. The features best differentiating the tumor-adjacent exocrine tissue from healthy control pancreas were defined by upregulation of proteins related to lipid transport. Importantly, histologically benign exocrine regions harbored the most significant prognostic pathways, with proteins involved in lipid transport and metabolism, such as neutral cholesteryl ester hydrolase 1, associating with shorter survival. In conclusion, this study reveals the prognostic molecular changes in the exocrine tissue neighboring pancreatic cancer and identifies enhanced lipid transport and metabolism as its defining features.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0396
  9. Nat Cell Biol. 2022 Sep 01.
    Identification of two pathways mediating protein targeting from ER to lipid droplets.
    Jiunn Song, Arda Mizrak, Chia-Wei Lee, Marcelo Cicconet, Zon Weng Lai, Wei-Chun Tang, Chieh-Han Lu, Stephanie E Mohr, Robert V Farese, Tobias C Walther.
      Pathways localizing proteins to their sites of action are essential for eukaryotic cell organization and function. Although mechanisms of protein targeting to many organelles have been defined, how proteins, such as metabolic enzymes, target from the endoplasmic reticulum (ER) to cellular lipid droplets (LDs) is poorly understood. Here we identify two distinct pathways for ER-to-LD protein targeting: early targeting at LD formation sites during formation, and late targeting to mature LDs after their formation. Using systematic, unbiased approaches in Drosophila cells, we identified specific membrane-fusion machinery, including regulators, a tether and SNARE proteins, that are required for the late targeting pathway. Components of this fusion machinery localize to LD-ER interfaces and organize at ER exit sites. We identified multiple cargoes for early and late ER-to-LD targeting pathways. Our findings provide a model for how proteins target to LDs from the ER either during LD formation or by protein-catalysed formation of membrane bridges.
    DOI:  https://doi.org/10.1038/s41556-022-00974-0
  10. Nat Commun. 2022 Sep 02. 13(1): 5164
    Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.
    Jonas Benjamin Michaelis, Melinda Elaine Brunstein, Süleyman Bozkurt, Ludovico Alves, Martin Wegner, Manuel Kaulich, Christian Pohl, Christian Münch.
      Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the mitochondrial outer membrane. Strikingly, a number of conditions, including mitochondrial protein misfolding, can induce mitophagy without a loss in membrane potential. The underlying molecular details remain unclear. Here, we report that a loss of mitochondrial protein import, mediated by the pre-sequence translocase-associated motor complex PAM, is sufficient to induce mitophagy in polarized mitochondria. A genome-wide CRISPR/Cas9 screen for mitophagy inducers identifies components of the PAM complex. Protein import defects are able to induce mitophagy without a need for depolarization. Upon mitochondrial protein misfolding, PAM dissociates from the import machinery resulting in decreased protein import and mitophagy induction. Our findings extend the current mitophagy model to explain mitophagy induction upon conditions that do not affect membrane polarization, such as mitochondrial protein misfolding.
    DOI:  https://doi.org/10.1038/s41467-022-32564-x
  11. Sci Adv. 2022 Sep 02. 8(35): eabo1215
    Phosphorylation of FAM134C by CK2 controls starvation-induced ER-phagy.
    Giorgia Di Lorenzo, Francescopaolo Iavarone, Marianna Maddaluno, Ana Belén Plata-Gómez, Simone Aureli, Camila Paz Quezada Meza, Laura Cinque, Alessandro Palma, Alessio Reggio, Carmine Cirillo, Francesca Sacco, Alexandra Stolz, Gennaro Napolitano, Oriano Marin, Lorenzo A Pinna, Maria Ruzzene, Vittorio Limongelli, Alejo Efeyan, Paolo Grumati, Carmine Settembre.
      Selective degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is initiated by ER-phagy receptors, which facilitate the incorporation of ER fragments into autophagosomes. FAM134 reticulon family proteins (FAM134A, FAM134B, and FAM134C) are ER-phagy receptors with structural similarities and nonredundant functions. Whether they respond differentially to the stimulation of ER-phagy is unknown. Here, we describe an activation mechanism unique to FAM134C during starvation. In fed conditions, FAM134C is phosphorylated by casein kinase 2 (CK2) at critical residues flanking the LIR domain. Phosphorylation of these residues negatively affects binding affinity to the autophagy proteins LC3. During starvation, mTORC1 inhibition limits FAM134C phosphorylation by CK2, hence promoting receptor activation and ER-phagy. Using a novel tool to study ER-phagy in vivo and FAM134C knockout mice, we demonstrated the physiological relevance of FAM134C phosphorylation during starvation-induced ER-phagy in liver lipid metabolism. These data provide a mechanistic insight into ER-phagy regulation and an example of autophagy selectivity during starvation.
    DOI:  https://doi.org/10.1126/sciadv.abo1215
  12. JAMA Oncol. 2022 Sep 01.
    Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial.
    Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group
       Importance: Early results at 3 years from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial showed survival benefits with adjuvant treatment with modified FOLFIRINOX vs gemcitabine in patients with resected pancreatic ductal adenocarcinoma; mature data are now available.
    Objective: To report 5-year outcomes and explore prognostic factors for overall survival.
    Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted at 77 hospitals in France and Canada and included patients aged 18 to 79 years with histologically confirmed pancreatic ductal adenocarcinoma who had undergone complete macroscopic (R0/R1) resection within 3 to 12 weeks before randomization. Patients were included from April 16, 2012, through October 3, 2016. The cutoff date for this analysis was June 28, 2021.
    Interventions: A total of 493 patients were randomized (1:1) to receive treatment with modified FOLFIRINOX (oxaliplatin, 85 mg/m2 of body surface area; irinotecan, 150-180 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 2400 mg/m2, every 2 weeks) or gemcitabine (1000 mg/m2, days 1, 8, and 15, every 4 weeks) as adjuvant therapy for 24 weeks.
    Main Outcomes and Measures: Primary end point was disease-free survival. Secondary end points included overall survival, metastasis-free survival, and cancer-specific survival. Prognostic factors for overall survival were determined.
    Results: Of the 493 patients, 216 (43.8%) were women, and the mean (SD) age was 62.0 (8.9) years. At a median of 69.7 months' follow-up, 367 disease-free survival events were observed. In patients receiving chemotherapy with modified FOLFIRINOX vs gemcitabine, median disease-free survival was 21.4 months (95% CI, 17.5-26.7) vs 12.8 months (95% CI, 11.6-15.2) (hazard ratio [HR], 0.66; 95% CI, 0.54-0.82; P < .001) and 5-year disease-free survival was 26.1% vs 19.0%; median overall survival was 53.5 months (95% CI, 43.5-58.4) vs 35.5 months (95% CI, 30.1-40.3) (HR, 0.68; 95% CI, 0.54-0.85; P = .001), and 5-year overall survival was 43.2% vs 31.4%; median metastasis-free survival was 29.4 months (95% CI, 21.4-40.1) vs 17.7 months (95% CI, 14.0-21.2) (HR, 0.64; 95% CI, 0.52-0.80; P < .001); and median cancer-specific survival was 54.7 months (95% CI, 45.8-68.4) vs 36.3 months (95% CI, 30.5-43.9) (HR, 0.65; 95% CI, 0.51-0.82; P < .001). Multivariable analysis identified modified FOLFIRINOX, age, tumor grade, tumor staging, and larger-volume center as significant favorable prognostic factors for overall survival. Shorter relapse delay was an adverse prognostic factor.
    Conclusions and Relevance: The final 5-year results from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial indicate that adjuvant treatment with modified FOLFIRINOX yields significantly longer survival than gemcitabine in patients with resected pancreatic ductal adenocarcinoma.
    Trial Registration: EudraCT: 2011-002026-52; ClinicalTrials.gov Identifier: NCT01526135.
    DOI:  https://doi.org/10.1001/jamaoncol.2022.3829
  13. Antioxid Redox Signal. 2022 Sep 02.
    The Interplay between Autophagy and Regulated Necrosis.
    Lei Zhang, Taixing Cui, Xuejun Wang.
       SIGNIFICANCE: Autophagy is critical to cellular homeostasis. Emergence of the concept of regulated necrosis, such as necroptosis, ferroptosis, pyroptosis, and MPT (mitochondrial membrane-permeability transition)-derived necrosis has revolutionized the research into necrosis. Both altered autophagy and regulated necrosis contribute to major human diseases. Recent studies reveal an intricate interplay between autophagy and regulated necrosis. Understanding the interplay at the molecular level will provide new insights into the pathophysiology of related diseases.
    RECENT ADVANCES: Among the three forms of autophagy, macroautophagy is better studied for its crosstalk with regulated necrosis. Macroautophagy seemingly can either antagonize or promote regulated necrosis, depending upon the form of regulated necrosis, the type of cells or stimuli, and other cellular context. This review will critically analyze recent advances in the molecular mechanisms governing the intricate dialogues between macroautophagy and main forms of regulated necrosis.
    CRITICAL ISSUES: The dual roles of autophagy, either pro-survival or pro-death characteristics intricate the mechanistic relationship between autophagy and regulated necrosis at molecular level in various pathological conditions. Meanwhile, key components of regulated necrosis are also involved in the regulation of autophagy, which further complicates the interrelationship.
    FUTURE DIRECTIONS: Resolving the controversies over causation between altered autophagy and a specific form of regulated necrosis requires approaches that are more definitive, where rigorous evaluation of autophagic flux and the development of more reliable and specific methods to quantify each form of necrosis will be essential. The relationship between chaperone-mediated autophagy or microautophagy and regulated necrosis remains largely unstudied.
    DOI:  https://doi.org/10.1089/ars.2022.0110
  14. Aging (Albany NY). 2022 Aug 29. 14(undefined):
    New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.
    Tomas Schmauck-Medina, Adrian Molière, Sofie Lautrup, Jianying Zhang, Stefan Chlopicki, Helena Borland Madsen, Shuqin Cao, Casper Soendenbroe, Els Mansell, Mark Bitsch Vestergaard, Zhiquan Li, Yosef Shiloh, Patricia L Opresko, Jean-Marc Egly, Thomas Kirkwood, Eric Verdin, Vilhelm A Bohr, Lynne S Cox, Tinna Stevnsner, Lene Juel Rasmussen, Evandro F Fang.
      Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the 'old' and 'new' hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.
    Keywords:  autophagy; hallmarks of ageing; healthspan; longevity; neurodegeneration
    DOI:  https://doi.org/10.18632/aging.204248
  15. Cell. 2022 Sep 01. pii: S0092-8674(22)00923-0. [Epub ahead of print]185(18): 3441-3456.e19
    Gut bacterial nutrient preferences quantified in vivo.
    Xianfeng Zeng, Xi Xing, Meera Gupta, Felix C Keber, Jaime G Lopez, Ying-Chiang J Lee, Asael Roichman, Lin Wang, Michael D Neinast, Mohamed S Donia, Martin Wühr, Cholsoon Jang, Joshua D Rabinowitz.
      Great progress has been made in understanding gut microbiomes' products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here, we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate, and urea (but not glucose or amino acids) feed the gut microbiome. To determine the nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We found systematic differences in nutrient use: most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.
    Keywords:  diet; host-microbiome interactions; isotope tracing; metabolism; metabolomics; methodology; mice; microbiome; nutrient; proteomics
    DOI:  https://doi.org/10.1016/j.cell.2022.07.020
  16. Sci Adv. 2022 Sep 02. 8(35): eabo7792
    Genome-wide in vivo screen of circulating tumor cells identifies SLIT2 as a regulator of metastasis.
    Fan Xia, Yuan Ma, Kangfu Chen, Bill Duong, Sharif Ahmed, Randy Atwal, David Philpott, Troy Ketela, Jennifer Pantea, Sichun Lin, Stephane Angers, Shana O Kelley.
      Circulating tumor cells (CTCs) break free from primary tumors and travel through the circulation system to seed metastatic tumors, which are the major cause of death from cancer. The identification of the major genetic factors that enhance production and persistence of CTCs in the bloodstream at a whole genome level would enable more comprehensive molecular mechanisms of metastasis to be elucidated and the identification of novel therapeutic targets, but this remains a challenging task due to the heterogeneity and extreme rarity of CTCs. Here, we describe an in vivo genome-wide CRISPR knockout screen using CTCs directly isolated from a mouse xenograft. This screen elucidated SLIT2-a gene encoding a secreted protein acting as a cellular migration cue-as the most significantly represented gene knockout in the CTC population. SLIT2 knockout cells are highly metastatic with hypermigratory and mesenchymal phenotype, resulting in enhanced cancer progression in xenograft models.
    DOI:  https://doi.org/10.1126/sciadv.abo7792
  17. Biochim Biophys Acta Rev Cancer. 2022 Aug 27. pii: S0304-419X(22)00110-X. [Epub ahead of print]1877(5): 188785
    AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene.
    Vasudevarao Penugurti, Yasaswi Gayatri Mishra, Bramanandam Manavathi.
      Metabolic reprogramming is a unique but complex biochemical adaptation that allows solid tumors to tolerate various stresses that challenge cancer cells for survival. Under conditions of metabolic stress, mammalian cells employ adenosine monophosphate (AMP)-activated protein kinase (AMPK) to regulate energy homeostasis by controlling cellular metabolism. AMPK has been described as a cellular energy sensor that communicates with various metabolic pathways and networks to maintain energy balance. Earlier studies characterized AMPK as a tumor suppressor in the context of cancer. Later, a paradigm shift occurred in support of the oncogenic nature of AMPK, considering it a contextual oncogene. In support of this, various cellular and mouse models of tumorigenesis and clinicopathological studies demonstrated increased AMPK activity in various cancers. This review will describe AMPK's pro-tumorigenic activity in various malignancies and explain the rationale and context for using AMPK inhibitors in combination with anti-metabolite drugs to treat AMPK-driven cancers.
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188785
  18. Mol Cell. 2022 Aug 25. pii: S1097-2765(22)00758-4. [Epub ahead of print]
    Life in lockdown: Orchestrating endoplasmic reticulum and lysosome homeostasis for quiescent cells.
    Andrew Murley, Kevin Wickham, Andrew Dillin.
      Cellular quiescence-reversible exit from the cell cycle-is an important feature of many cell types important for organismal health. Quiescent cells activate protective mechanisms that allow their persistence in the absence of growth and division for long periods of time. Aging and cellular dysfunction compromise the survival and re-activation of quiescent cells over time. Counteracting this decline are two interconnected organelles that lie at opposite ends of the secretory pathway: the endoplasmic reticulum and lysosomes. In this review, we highlight recent studies exploring the roles of these two organelles in quiescent cells from diverse contexts and speculate on potential other roles they may play, such as through organelle contact sites. Finally, we discuss emerging models of cellular quiescence, utilizing new cell culture systems and model organisms, that are suited to the mechanistic investigation of the functions of these organelles in quiescent cells.
    Keywords:  ER; aging; lysosome; quiescence; stem cells
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.005
  19. J Cell Sci. 2022 Sep 02. pii: jcs.259856. [Epub ahead of print]
    The histone methyltransferase SETD2 negatively regulates cell size.
    Thom M Molenaar, Muddassir Malik, Joana Silva, Ning Qing Liu, Judith H I Haarhuis, Christina Ambrosi, Eliza Mari Kwesi-Maliepaard, Tibor van Welsem, Tuncay Baubec, William J Faller, Fred van Leeuwen.
      Cell size varies between cell types but is tightly regulated by cell-intrinsic and extrinsic mechanisms. Cell-size control is important for cell function and changes in cell size are frequently observed in cancer. Here we uncover a role for SETD2 in regulating cell size. SETD2 is a lysine methyltransferase and a tumor suppressor protein involved in transcription, RNA processing and DNA repair. At the molecular level, SETD2 is best known for associating with RNA polymerase II through its Set2-Rbp1 interacting (SRI) domain and methylating histone H3 on lysine 36 (H3K36) during transcription. Using multiple, independent perturbation strategies we identify SETD2 as a negative regulator of global protein synthesis rates and cell size. We provide evidence that overexpression of the H3K36 demethylase KDM4A or the oncohistone H3.3K36M also increase cell size. In addition, ectopic overexpression of a decoy SRI domain increased cell size, suggesting that the relevant substrate is engaged by SETD2 via its SRI domain. These data add a central role of SETD2 in regulating cellular physiology and warrant further studies on separating the different functions of SETD2 in cancer development.
    Keywords:  Cell size; Chromatin; Histone methyltransferase; KDM4A; SETD2
    DOI:  https://doi.org/10.1242/jcs.259856
  20. Hum Cell. 2022 Sep 01.
    SQSTM1/p62 promotes miR-198 loading into extracellular vesicles and its autophagy-related secretion.
    Xiaojie Yu, Hannah Eischeid-Scholz, Lydia Meder, Vangelis Kondylis, Reinhard Büttner, Margarete Odenthal.
      MicroRNA dysregulation is a hallmark of hepatocellular carcinoma (HCC), leading to tumor growth and metastasis. Previous screening on patient specimens identified miR-198 as the most downregulated miRNA in HCC. Here, we show that miR-198 compensation leads to self-release into extracellular vesicles (EVs). Importantly, the vesicular secretion is mediated by autophagy-related pathway, initiated by sequestration of p62/miR-198 complexes in autophagosome-associated vesicle fractions. miR-198 is selectively recognized and loaded by p62 into autophagosomal fractions, whereas mutated miR-198 forms neither induce autophagy and nor interact with p62. Gain and loss of function experiments, using a CRIPR/Cas knockout (KO) and transgenic site-specific p62 mutants, identified p62 as an essential repressor of cellular miR-198 abundancy. Notably, EVs, harboring miR-198/p62 protein complexes, can be uptaken by cells in the close vicinity, leading to change of gene expression in recipient cells. In conclusion, miR-198 enhances autophagy; conversely autophagic protein p62 reduces the miR-198 levels by sorting into extracellular space. miR-198 is at first transcribed as primary miRNA, after being processed into single stranded mature miR-198 form, it is transported into cytoplasm ①. By interaction with p62 protein, miR-198 conglomerates and forms a binding complex ②. Since LC3 protein is an interaction partner of p62 protein, hence miR-198 is included into autophagosomes ③. By fusion with multivesicular bodies (MVB), miR-198-binding complex was recruited into amphisomes ④, the latter of which quickly turns into secretory MVB containing intraluminal vesicles⑤. By fusion with cell membrane, intraluminal vesicles were released into extracellular space as EVs ⑥.
    Keywords:  Autophagy; EV; HCC; SQSTM1; microRNA
    DOI:  https://doi.org/10.1007/s13577-022-00765-7
  21. Mol Biol Cell. 2022 Aug 31. mbcE22040139
    The endoplasmic reticulum contributes to lysosomal tubulation/sorting driven by LRRK2.
    Luis Bonet-Ponce, Mark R Cookson.
      Lysosomes are dynamic organelles that can remodel their membrane as an adaptive response to various cell signaling events including membrane damage. Recently, we have discovered that damaged lysosomes form and sort tubules into moving vesicles. We named this process LYTL for LYsosomal Tubulation/ sorting driven by LRRK2, as the Parkinson's disease protein LRRK2 promotes tubulation by recruiting the motor adaptor protein JIP4 to lysosomes via phosphorylated RAB proteins. Here we use spinning-disk microscopy combined with super-resolution to further characterize LYTL after membrane damage with LLOMe. We identified the endoplasmic reticulum (ER) colocalizing with sites of fission of lysosome-derived tubules. In addition, modifying the morphology of the ER by reducing ER tubules leads to a decrease in LYTL sorting suggesting that contact with tubular ER is necessary for lysosomal membrane sorting. Given the central roles of LRRK2 and lysosomal biology in PD, these discoveries are likely relevant to disease pathology and highlight interactions between organelles in this model. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E22-04-0139
  22. J Cell Sci. 2022 Sep 02. pii: jcs.259701. [Epub ahead of print]
    Nucleolar targeting in an early-branching eukaryote suggests a general mechanism for ribosome protein sorting.
    Milad Jeilani, Karen Billington, Jack Daniel Sunter, Samuel Dean, Richard John Wheeler.
      The compartmentalised eukaryotic cell demands accurate targeting of proteins to the organelles in which they function, whether membrane-bound (like the nucleus) or non-membrane-bound (like the nucleolus). Nucleolar targeting relies on positively charged localisation signals, and has received rejuvenated interest since the widespread recognition of liquid-liquid phase separation (LLPS) as a mechanism contributing to nucleolus formation. Here, we exploit a new genome-wide analysis of protein localisation in an early-branching eukaryote, Trypanosoma brucei, to analyse general nucleolar protein properties. T. brucei nucleolar proteins have similar properties to those in common model eukaryotes, specifically basic amino acids. Using protein truncations and addition of candidate targeting sequences to proteins, we show both homopolymer runs and distributed basic amino acids give nucleolar partition, further aided by a nuclear localisation signal (NLS). These findings are consistent with phase separation models of nucleolar formation and protein physical properties being a major contributing mechanism for eukaryotic nucleolar targeting, conserved from the last eukaryotic common ancestor. Importantly, cytoplasmic ribosome proteins unlike mitochondrial ribosome proteins have more basic residues - pointing to adaptation of physicochemical properties to assist segregation.
    Keywords:  Liquid-liquid phase separation; Mitochondrial ribosome; Nucleolar targeting; Nucleolus; Trypanosome
    DOI:  https://doi.org/10.1242/jcs.259701
  23. J Cell Biol. 2022 Sep 05. pii: e202205123. [Epub ahead of print]221(9):
    Quality control mechanisms that protect nuclear envelope identity and function.
    Philip J Mannino, C Patrick Lusk.
      The nuclear envelope (NE) is a specialization of the endoplasmic reticulum with distinct biochemistry that defines inner and outer membranes connected at a pore membrane that houses nuclear pore complexes (NPCs). Quality control mechanisms that maintain the physical integrity and biochemical identity of these membranes are critical to ensure that the NE acts as a selective barrier that also contributes to genome stability and metabolism. As the proteome of the NE is highly integrated, it is challenging to turn over by conventional ubiquitin-proteasome and autophagy mechanisms. Further, removal of entire sections of the NE requires elaborate membrane remodeling that is poorly understood. Nonetheless, recent work has made inroads into discovering specializations of cellular degradative machineries tailored to meeting the unique challenges imposed by the NE. In addition, cells have evolved mechanisms to surveil and repair the NE barrier to protect against the deleterious effects of a breach in NE integrity, in the form of either a ruptured NE or a dysfunctional NPC. Here, we synthesize the most recent work exploring NE quality control mechanisms across eukaryotes.
    DOI:  https://doi.org/10.1083/jcb.202205123
  24. J Immunother Precis Oncol. 2022 Aug;5(3): 58-67
    Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors in Oncology Clinical Trials: A review.
    Kavanya Feustel, Gerald S Falchook.
      Protein arginine methyltransferase 5 (PRMT5) inhibitors are a new class of antineoplastic agents showing promising preliminary clinical efficacy. Targeting an enzyme involved in a wide array of cellular and transcriptional pro-oncogenic processes, this class offers multifaceted tumor-suppressive effects. Partial response has been seen in adenoid cystic carcinoma from both GSK3326595 and JNJ-64619178, with four cases of stable disease seen with PRT543. Highly significant is a durable complete response in isocitrate dehydrogenase 1-mutated glioblastoma multiforme with PRT811. Both alone and in combination with existing chemotherapies and immunotherapies, this class shows promising preliminary data, particularly in cancers with splicing mutations and DNA damage repair deficiencies. Further studies are warranted, and there are clinical trials to come whose data will be telling of the efficacy of PRMT5 inhibitors in both hematologic and solid malignancies. The aim of this study is to compile available results of PRMT5 inhibitors in oncology clinical trials.
    Keywords:  PRMT5; cancer; clinical trial; histone; protein arginine methyltransferase; review; splicing
    DOI:  https://doi.org/10.36401/JIPO-22-1
  25. Autophagy. 2022 Sep 02. 1-3
    Involvement of acetylation of ATG4B in controlling autophagy induction.
    Haojun Xiong, Liangbo Sun, Jiqin Lian, Fengtian He.
      ATG4B, a cysteine protease promoting autophagosome formation by reversibly modifying Atg8-family proteins, plays a vital role in controlling macroautophagy/autophagy initiation in response to stress. However, the molecular mechanism underlying the regulation of ATG4B activity is far from well elucidated. In the current study, we firstly revealed that the acetylation level of ATG4B at lysine residue 39 (K39) is strongly involved in regulating its activity and autophagy. Specifically, SIRT2 deacetylates ATG4B K39, enhancing ATG4B activity and autophagic flux, which can be antagonized by EP300/p300. Starvation treatment contributes to EP300 suppression and SIRT2 activation, promoting the deacetylation of ATG4B K39, which leads to the elevation of ATG4B activity and finally autophagy initiation. Mechanistic investigation showed that starvation reduces CCNE (cyclin E), resulting in the downregulation of the CCNE-CDK2 protein complex, decreasing the phosphorylation of SIRT2 Ser331 and finally activating SIRT2. In addition, we confirmed that SIRT2 promotes autophagy via suppressing acetylation of ATG4B at K39 using sirt2 gene knockout (sirt2-/-) mice. Collectively, our results have revealed the acetylation-mediated regulation of ATG4B cysteine protease activity in autophagy initiation in response to nutritional deficiency.
    Keywords:  ATG4B; Acetylation; EP300; SIRT2; autophagy; starvation
    DOI:  https://doi.org/10.1080/15548627.2022.2117887
  26. Sci Adv. 2022 Sep 02. 8(35): eabq5206
    Operation of a TCA cycle subnetwork in the mammalian nucleus.
    Eleni Kafkia, Amparo Andres-Pons, Kerstin Ganter, Markus Seiler, Tom S Smith, Anna Andrejeva, Paula Jouhten, Filipa Pereira, Catarina Franco, Anna Kuroshchenkova, Sergio Leone, Ritwick Sawarkar, Rebecca Boston, James Thaventhiran, Judith B Zaugg, Kathryn S Lilley, Christophe Lancrin, Martin Beck, Kiran Raosaheb Patil.
      Nucleic acid and histone modifications critically depend on the tricarboxylic acid (TCA) cycle for substrates and cofactors. Although a few TCA cycle enzymes have been reported in the nucleus, the corresponding pathways are considered to operate in mitochondria. Here, we show that a part of the TCA cycle is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Nuclear localization of the latter enzyme, which produces succinyl-CoA, changed from pluripotency to a differentiated state with accompanying changes in the nuclear protein succinylation. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus, warranting a revision of the canonical view on metabolic compartmentalization.
    DOI:  https://doi.org/10.1126/sciadv.abq5206
  27. NPJ Breast Cancer. 2022 Sep 02. 8(1): 101
    Assessment of MRI to estimate metastatic dissemination risk and prometastatic effects of chemotherapy.
    George S Karagiannis, Anthony Bianchi, Luis Rivera Sanchez, Kamal Ambadipudi, Min-Hui Cui, Jesus M Anampa, Saeed Asiry, Yarong Wang, Allison S Harney, Jessica M Pastoriza, Yu Lin, Xiaoming Chen, Joan G Jones, David Entenberg, Dana Haddad, Laura J Hodges, Timothy Q Duong, Joseph A Sparano, Maja H Oktay, Craig A Branch, John S Condeelis.
      Metastatic dissemination in breast cancer is regulated by specialized intravasation sites called "tumor microenvironment of metastasis" (TMEM) doorways, composed of a tumor cell expressing the actin-regulatory protein Mena, a perivascular macrophage, and an endothelial cell, all in stable physical contact. High TMEM doorway number is associated with an increased risk of distant metastasis in human breast cancer and mouse models of breast carcinoma. Here, we developed a novel magnetic resonance imaging (MRI) methodology, called TMEM Activity-MRI, to detect TMEM-associated vascular openings that serve as the portal of entry for cancer cell intravasation and metastatic dissemination. We demonstrate that TMEM Activity-MRI correlates with primary tumor TMEM doorway counts in both breast cancer patients and mouse models, including MMTV-PyMT and patient-derived xenograft models. In addition, TMEM Activity-MRI is reduced in mouse models upon treatment with rebastinib, a specific and potent TMEM doorway inhibitor. TMEM Activity-MRI is an assay that specifically measures TMEM-associated vascular opening (TAVO) events in the tumor microenvironment, and as such, can be utilized in mechanistic studies investigating molecular pathways of cancer cell dissemination and metastasis. Finally, we demonstrate that TMEM Activity-MRI increases upon treatment with paclitaxel in mouse models, consistent with prior observations that chemotherapy enhances TMEM doorway assembly and activity in human breast cancer. Our findings suggest that TMEM Activity-MRI is a promising precision medicine tool for localized breast cancer that could be used as a non-invasive test to determine metastatic risk and serve as an intermediate pharmacodynamic biomarker to monitor therapeutic response to agents that block TMEM doorway-mediated dissemination.
    DOI:  https://doi.org/10.1038/s41523-022-00463-5
  28. Elife. 2022 Aug 30. pii: e79283. [Epub ahead of print]11
    Nuclear fascin regulates cancer cell survival.
    Campbell D Lawson, Samantha Peel, Asier Jayo, Adam Corrigan, Preeti Iyer, Mabel Baxter Dalrymple, Richard J Marsh, Susan Cox, Isabel Van Audenhove, Jan Gettemans, Maddy Parsons.
      Fascin is an important regulator of F-actin bundling leading to enhanced filopodia assembly. Fascin is also overexpressed in most solid tumours where it supports invasion through control of F-actin structures at the periphery and nuclear envelope. Recently, fascin has been identified in the nucleus of a broad range of cell types but the contributions of nuclear fascin to cancer cell behaviour remain unknown. Here, we demonstrate that fascin bundles F-actin within the nucleus to support chromatin organisation and efficient DDR. Fascin associates directly with phosphorylated Histone H3 leading to regulated levels of nuclear fascin to support these phenotypes. Forcing nuclear fascin accumulation through the expression of nuclear-targeted fascin-specific nanobodies or inhibition of Histone H3 kinases results in enhanced and sustained nuclear F-actin bundling leading to reduced invasion, viability, and nuclear fascin-specific/driven apoptosis. These findings represent an additional important route through which fascin can support tumourigenesis and provide insight into potential pathways for targeted fascin-dependent cancer cell killing.
    Keywords:  actin; apoptosis; cancer; cancer biology; cell biology; fascin; human; invasion; nucleus
    DOI:  https://doi.org/10.7554/eLife.79283
  29. Cancer Cell. 2022 Aug 26. pii: S1535-6108(22)00375-0. [Epub ahead of print]
    Clinical application of advanced multi-omics tumor profiling: Shaping precision oncology of the future.
    Dilara Akhoundova, Mark A Rubin.
      Next-generation DNA sequencing technology has dramatically advanced clinical oncology through the identification of therapeutic targets and molecular biomarkers, leading to the personalization of cancer treatment with significantly improved outcomes for many common and rare tumor entities. More recent developments in advanced tumor profiling now enable dissection of tumor molecular architecture and the functional phenotype at cellular and subcellular resolution. Clinical translation of high-resolution tumor profiling and integration of multi-omics data into precision treatment, however, pose significant challenges at the level of prospective validation and clinical implementation. In this review, we summarize the latest advances in multi-omics tumor profiling, focusing on spatial genomics and chromatin organization, spatial transcriptomics and proteomics, liquid biopsy, and ex vivo modeling of drug response. We analyze the current stages of translational validation of these technologies and discuss future perspectives for their integration into precision treatment.
    Keywords:  cancer biomarkers; ex vivo modeling; liquid biopsy; precision treatment; spatial multi-omics; tumor molecular profiling
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.011
  30. Int J Cancer. 2022 Sep 02.
    FOLFIRINOX or gemcitabine/nab-paclitaxel in advanced pancreatic adenocarcinoma - A novel validated prognostic score to facilitate treatment decision-making in real-world.
    TPK-Group (Tumour Registry Pancreatic Cancer)
      There is no prospective, randomised head-to-head trial comparing first-line FOLFIRINOX and gemcitabine/nab-paclitaxel in advanced pancreatic cancer. We assess real-world effectiveness and quality of life (QoL) of both regimens using a new prognostic score. This analysis includes 1,540 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer separated into learning (n=1,027) and validation sample (n=513). The Pancreatic Cancer Score (PCS) was developed using multivariate Cox regression. We compared overall survival (OS) and time to deterioration (TTD) for longitudinal QoL between first-line FOLFIRINOX (n=407) and gemcitabine/nab-paclitaxel (n=655) according to patients' prognostic risk, after inverse probability of treatment weighting (IPTW) by propensity score analysis. The PCS includes nine independent prognostic factors for survival: female sex, BMI ≥24/unknown, ECOG performance status ≥1, Charlson comorbidity index ≥1, tumour staging IV/unknown at primary diagnosis, liver metastases, bilirubin >1.5x upper limit of normal (ULN), leukocytes >ULN and neutrophil-to-lymphocyte ratio ≥4. Median OS of the validation sample was 11.4 (95%-CI 10.4-14.4), 8.5 (95%-CI 6.8-9.6) and 5.9 months (95%-CI 4.0-7.4) for favourable- (0-3 risk factors), intermediate- (4-5 factors) and poor-risk group (6-9 factors), respectively. After IPTW, only poor-risk patients had significantly longer median OS and TTD of overall QoL with FOLFIRINOX (OS: 6.9 months, 95%-CI 3.9-13.3; TTD: 10.6 months, 95%-CI 2.0-14.1) versus gemcitabine/nab-paclitaxel (OS: 4.0 months, 95%-CI 2.8-4.8; TTD: 4.1 months, 95%-CI 2.4-4.5). Our novel PCS may facilitate treatment decisions in clinical routine of advanced pancreatic cancer, since only poor-risk, but not favourable-risk patients, seem to benefit from intensified treatment with FOLFIRINOX. This article is protected by copyright. All rights reserved.
    Keywords:  Cohort Studies; FOLFIRINOX; Gemcitabine/nab-Paclitaxel; Pancreatic Carcinoma; Prognostic Score
    DOI:  https://doi.org/10.1002/ijc.34271
  31. Nat Rev Cancer. 2022 Aug 31.
    Resolving the spatial heterogeneity of cancer in 3D.
    Anne C Rios.
      
    DOI:  https://doi.org/10.1038/s41568-022-00506-w
  32. Nature. 2022 Aug 31.
    The role of somatosensory innervation of adipose tissues.
    Yu Wang, Verina H Leung, Yunxiao Zhang, Victoria S Nudell, Meaghan Loud, M Rocio Servin-Vences, Dong Yang, Kristina Wang, Maria Dolores Moya-Garzon, Veronica L Li, Jonathan Z Long, Ardem Patapoutian, Li Ye.
      Adipose tissues communicate with the central nervous system to maintain whole-body energy homeostasis. The mainstream view is that circulating hormones secreted by the fat convey the metabolic state to the brain, which integrates peripheral information and regulates adipocyte function through noradrenergic sympathetic output1. Moreover, somatosensory neurons of the dorsal root ganglia innervate adipose tissue2. However, the lack of genetic tools to selectively target these neurons has limited understanding of their physiological importance. Here we developed viral, genetic and imaging strategies to manipulate sensory nerves in an organ-specific manner in mice. This enabled us to visualize the entire axonal projection of dorsal root ganglia from the soma to subcutaneous adipocytes, establishing the anatomical underpinnings of adipose sensory innervation. Functionally, selective sensory ablation in adipose tissue enhanced the lipogenic and thermogenetic transcriptional programs, resulting in an enlarged fat pad, enrichment of beige adipocytes and elevated body temperature under thermoneutral conditions. The sensory-ablation-induced phenotypes required intact sympathetic function. We postulate that beige-fat-innervating sensory neurons modulate adipocyte function by acting as a brake on the sympathetic system. These results reveal an important role of the innervation by dorsal root ganglia of adipose tissues, and could enable future studies to examine the role of sensory innervation of disparate interoceptive systems.
    DOI:  https://doi.org/10.1038/s41586-022-05137-7
  33. Nature. 2022 Aug 31.
    Almost half of cancer deaths are preventable.
    Giorgia Guglielmi.
      
    Keywords:  Cancer; Obesity; Public health
    DOI:  https://doi.org/10.1038/d41586-022-02355-x
  34. Mol Cell. 2022 Aug 23. pii: S1097-2765(22)00761-4. [Epub ahead of print]
    Ubiquitination of phosphatidylethanolamine in organellar membranes.
    Jun-Ichi Sakamaki, Koji L Ode, Yoshitaka Kurikawa, Hiroki R Ueda, Hayashi Yamamoto, Noboru Mizushima.
      The covalent conjugation of ubiquitin family proteins is a widespread post-translational protein modification. In the ubiquitin family, the ATG8 subfamily is exceptional because it is conjugated mainly to phospholipids. However, it remains unknown whether other ubiquitin family proteins are also conjugated to phospholipids. Here, we report that ubiquitin is conjugated to phospholipids, mainly phosphatidylethanolamine (PE), in yeast and mammalian cells. Ubiquitinated PE (Ub-PE) accumulates at endosomes and the vacuole (or lysosomes), and its level increases during starvation. Ub-PE is also found in baculoviruses. In yeast, PE ubiquitination is catalyzed by the canonical ubiquitin system enzymes Uba1 (E1), Ubc4/5 (E2), and Tul1 (E3) and is reversed by Doa4. Liposomes containing Ub-PE recruit the ESCRT components Vps27-Hse1 and Vps23 in vitro. Ubiquitin-like NEDD8 and ISG15 are also conjugated to phospholipids. These findings suggest that the conjugation to membrane phospholipids is not specific to ATG8 but is a general feature of the ubiquitin family.
    Keywords:  Doa4; Tul1; endosome; lysosome; phosphatidylethanolamine; phospholipids; ubiquitin; ubiquitin-like proteins; vacuole
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.008
  35. STAR Protoc. 2022 Sep 16. 3(3): 101611
    Imaging and analysis for simultaneous tracking of fluorescent biosensors in barcoded cells.
    Wei-Yu Chi, Gabriel Au, Jessica Liang, Chao-Cheng Chen, Chuan-Hsiang Huang, Jr-Ming Yang.
      We recently developed a biosensor barcoding approach for highly multiplexed tracking of molecular activities in live cells. In this protocol, we detail the labeling of cells expressing different genetically encoded fluorescent biosensors with a pair of barcoding proteins and parallel imaging. Signals from cells with the same barcodes are then pooled together to obtain the dynamics of the corresponding biosensor activity. We describe the steps involved in cell barcoding, image acquisition, and analysis by deep learning models. For complete details on the use and execution of this protocol, please refer to Yang et al. (2021).
    Keywords:  Cell biology; Microscopy; Molecular/Chemical probes; Signal transduction; Single cell
    DOI:  https://doi.org/10.1016/j.xpro.2022.101611
  36. Lab Invest. 2022 Aug 31.
    Simultaneous metabolite MALDI-MSI, whole exome and transcriptome analysis from formalin-fixed paraffin-embedded tissue sections.
    Lisa Kreutzer, Peter Weber, Theresa Heider, Mathias Heikenwälder, Tobias Riedl, Philipp Baumeister, Frederick Klauschen, Claus Belka, Axel Walch, Horst Zitzelsberger, Julia Hess, Kristian Unger.
      Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) allows spatial analysis of proteins, metabolites, or small molecules from tissue sections. Here, we present the simultaneous generation and analysis of MALDI-MSI, whole-exome sequencing (WES), and RNA-sequencing data from the same formalin-fixed paraffin-embedded (FFPE) tissue sections. Genomic DNA and total RNA were extracted from (i) untreated, (ii) hematoxylin-eosin (HE) stained, and (iii) MALDI-MSI-analyzed FFPE tissue sections from three head and neck squamous cell carcinomas. MALDI-MSI data were generated by a time-of-flight analyzer prior to preprocessing and visualization. WES data were generated using a low-input protocol followed by detection of single-nucleotide variants (SNVs), tumor mutational burden, and mutational signatures. The transcriptome was determined using 3'-RNA sequencing and was examined for similarities and differences between processing stages. All data met the commonly accepted quality criteria. Besides SNVs commonly identified between differently processed tissues, FFPE-typical artifactual variants were detected. Tumor mutational burden was in the same range for tissues from the same patient and mutational signatures were highly overlapping. Transcriptome profiles showed high levels of correlation. Our data demonstrate that simultaneous molecular profiling of MALDI-MSI-processed FFPE tissue sections at the transcriptome and exome levels is feasible and reliable.
    DOI:  https://doi.org/10.1038/s41374-022-00829-0
  37. Nat Rev Drug Discov. 2022 Aug 31.
    The improving benefit-risk balance of phase I cancer trials.
    Katie Kingwell.
      
    DOI:  https://doi.org/10.1038/d41573-022-00144-9
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