bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2021–08–01
37 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Host autophagy mediates organ wasting and nutrient mobilization for tumor growth.
  2. ANGPTL4 accelerates KRASG12D-Induced acinar to ductal metaplasia and pancreatic carcinogenesis.
  3. PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma.
  4. Cell death in pancreatic cancer: from pathogenesis to therapy.
  5. AGR2-dependent nuclear import of RNA polymerase II constitutes a specific target of pancreatic ductal adenocarcinoma in the context of wild-type p53.
  6. Future directions in preclinical and translational cancer neuroscience research.
  7. CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions.
  8. Modeling metastasis in mice: a closer look.
  9. From bench to bedside: single-cell analysis for cancer immunotherapy.
  10. All cells are created equal in the sight of autophagy: selective autophagy maintains homeostasis in senescent cells.
  11. Discovery and 3D imaging of a novel ΔNp63-expressing basal cell type in human pancreatic ducts with implications in disease.
  12. Calcium signaling induces a partial EMT.
  13. Cell cycle on the crossroad of tumorigenesis and cancer therapy.
  14. Roles of Phase Separation for Cellular Redox Maintenance.
  15. [18F]FDG PET/MRI enables early chemotherapy response prediction in pancreatic ductal adenocarcinoma.
  16. ATG4s: above and beyond the Atg8-family protein lipidation system.
  17. A pancreas tumor derived organoid study: from drug screen to precision medicine.
  18. Anti-cachexia therapy should target metabolism, inflammatory cytokines, and androgens in hormone-independent cancers.
  19. Pancreatic specific CHRM3 activation causes pancreatitis in mice.
  20. The immunological and metabolic landscape in primary and metastatic liver cancer.
  21. Caveolin-1 increases glycolysis in pancreatic cancer cells and triggers cachectic states.
  22. Tissue clearing to examine tumour complexity in three dimensions.
  23. HMGs as rheostats of chromosomal structure and cell proliferation.
  24. The Cancer SENESCopedia: A delineation of cancer cell senescence.
  25. Super-resolution microscopy reveals the arrangement of inner membrane protein complexes in mammalian mitochondria.
  26. The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.
  27. Sequential oncogenic mutations influence cell competition.
  28. TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells.
  29. Tanycytic networks mediate energy balance by feeding lactate to glucose-insensitive POMC neurons.
  30. Control of condensates dictates nucleolar architecture.
  31. Features of age-related response to sleep deprivation: in vivo experimental studies.
  32. Monitoring selective autophagy of mitochondria using super-resolution microscopy.
  33. Cellular senescence or stemness: hypoxia flips the coin.
  34. Multiplexed Imaging of Posttranslational Modifications of Endogenous Proteins in Live Cells.
  35. T cell stiffness is enhanced upon formation of immunological synapse.
  36. Mutational signatures: emerging concepts, caveats and clinical applications.
  37. The dynamic nature of the K-Ras/calmodulin complex can be altered by oncogenic mutations.
  1. EMBO J. 2021 Jul 26. e107336
    Host autophagy mediates organ wasting and nutrient mobilization for tumor growth.
    Rojyar Khezri, Petter Holland, Todd Andrew Schoborg, Ifat Abramovich, Szabolcs Takáts, Caroline Dillard, Ashish Jain, Fergal O'Farrell, Sebastian Wolfgang Schultz, William M Hagopian, Eduardo Martin Quintana, Rachel Ng, Nadja Sandra Katheder, Mohammed Mahidur Rahman, José Gerardo Teles Reis, Andreas Brech, Heinrich Jasper, Nasser M Rusan, Anne Hope Jahren, Eyal Gottlieb, Tor Erik Rusten.
      During tumor growth-when nutrient and anabolic demands are high-autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that RasV12 ; scrib-/- tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.
    Keywords:   Drosophila ; autophagy; cancer cachexia; muscle; tumor; wasting
    DOI:  https://doi.org/10.15252/embj.2020107336
  2. Cancer Lett. 2021 Jul 24. pii: S0304-3835(21)00369-4. [Epub ahead of print]519 185-198
    ANGPTL4 accelerates KRASG12D-Induced acinar to ductal metaplasia and pancreatic carcinogenesis.
    Hong Hua Yan, Kyung Hee Jung, Ji Eun Lee, Mi Kwon Son, Zhenghuan Fang, Jung Hee Park, Soo Jung Kim, Ju Young Kim, Ju Han Lim, Soon-Sun Hong.
      Oncogenic KRASG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), and drives pancreatic ductal adenocarcinoma (PDAC). Angiopoietin-like 4 (ANGPTL4) is known to be involved in the regulation of cancer growth and metastasis. However, whether ANGPTL4 affects KRASG12D-mediated ADM and early PDAC intervention remains unknown. In the current study, we investigated the role of ANGPTL4 in KRASG12D-induced ADM, PanIN formation, and PDAC maintenance. We found that ANGPTL4 was highly expressed in human and mouse ADM lesions and contributed to the promotion of KRASG12D-driven ADM in mice. Consistently, ANGPTL4 rapidly induced ADM in three-dimensional culture of acinar cells with KRAS mutation and formed ductal cysts that silenced acinar genes and activated ductal genes, which are characteristic of in vivo ADM/PanIN lesions. We also found that periostin works as a downstream regulator of ANGPTL4-mediated ADM/PDAC. Genetic ablation of periostin diminished the ADM/PanIN phenotype induced by ANGPTL4. A high correlation between ANGPTL4 and periostin was confirmed in human samples. These results demonstrate that ANGPTL4 is critical for ADM/PanIN initiation and PDAC progression through the regulation of periostin. Thus, the ANGPTL4/periostin axis is considered a potential target for ADM-derived PDAC.
    Keywords:  ADM; ANGPTL4; PDAC; PanIN; Periostin
    DOI:  https://doi.org/10.1016/j.canlet.2021.07.036
  3. Nat Commun. 2021 Jul 30. 12(1): 4626
    PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma.
    Virginia Giuliani, Meredith A Miller, Chiu-Yi Liu, Stella R Hartono, Caleb A Class, Christopher A Bristow, Erika Suzuki, Lionel A Sanz, Guang Gao, Jason P Gay, Ningping Feng, Johnathon L Rose, Hideo Tomihara, Joseph R Daniele, Michael D Peoples, Jennifer P Bardenhagen, Mary K Geck Do, Qing E Chang, Bhavatarini Vangamudi, Christopher Vellano, Haoqiang Ying, Angela K Deem, Kim-Anh Do, Giannicola Genovese, Joseph R Marszalek, Jeffrey J Kovacs, Michael Kim, Jason B Fleming, Ernesto Guccione, Andrea Viale, Anirban Maitra, M Emilia Di Francesco, Timothy A Yap, Philip Jones, Giulio Draetta, Alessandro Carugo, Frederic Chedin, Timothy P Heffernan.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.Statement of significancePDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.
    DOI:  https://doi.org/10.1038/s41467-021-24798-y
  4. Nat Rev Gastroenterol Hepatol. 2021 Jul 30.
    Cell death in pancreatic cancer: from pathogenesis to therapy.
    Xin Chen, Herbert J Zeh, Rui Kang, Guido Kroemer, Daolin Tang.
      Pancreatic cancer is a devastating gastrointestinal cancer characterized by late diagnosis, limited treatment success and dismal prognosis. Exocrine tumours account for 95% of pancreatic cancers and the most common pathological type is pancreatic ductal adenocarcinoma (PDAC). The occurrence and progression of PDAC involve multiple factors, including internal genetic alterations and external inflammatory stimuli. The biology and therapeutic response of PDAC are further shaped by various forms of regulated cell death, such as apoptosis, necroptosis, ferroptosis, pyroptosis and alkaliptosis. Cell death induced by local or systemic treatments suppresses tumour proliferation, invasion and metastasis. However, unrestricted cell death or tissue damage might result in an inflammation-related immunosuppressive microenvironment, which is conducive to tumour progression or recurrence. The precise extent to which cell death affects PDAC is not yet well described. A growing body of preclinical and clinical studies document significant correlations between mutations (for example, in KRAS and TP53), stress responses (such as hypoxia and autophagy), metabolic reprogramming and chemotherapeutic responses. Here, we describe the molecular machinery of cell death, discuss the complexity and multifaceted nature of lethal signalling in PDAC cells, and highlight the challenges and opportunities for activating cell death pathways through precision oncology treatments.
    DOI:  https://doi.org/10.1038/s41575-021-00486-6
  5. Gastroenterology. 2021 Jul 22. pii: S0016-5085(21)03281-9. [Epub ahead of print]
    AGR2-dependent nuclear import of RNA polymerase II constitutes a specific target of pancreatic ductal adenocarcinoma in the context of wild-type p53.
    Zhiheng Zhang, Hongzhen Li, Yibin Deng, Kathleen Schuck, Susanne Raulefs, Nadja Maeritz, Yuanyuan Yu, Torsten Hechler, Andreas Pahl, Vanesa Fernández-Sáiz, Yuan Wan, Guosheng Wang, Thomas Engleitner, Rupert Öllinger, Roland Rad, Maximilian Reichert, Kalliope N Diakopoulos, Verena Weber, Jingjing Li, Shanshan Shen, Xiaoping Zou, Jörg Kleeff, Andre Mihaljevic, Christoph W Michalski, Hana Algül, Helmut Friess, Bo Kong.
       BACKGROUND AND AIM: Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Agr2 (anterior gradient 2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target.
    METHODS: A mouse model of inflammation-accelerated KrasG12D-driven ADM and PanIN development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex.
    RESULTS: We found that Agr2 is upregulated in ADM-to-PanIN transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Since Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harbouring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types.
    CONCLUSION: Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.
    Keywords:  Agr2; hexapeptide; metaplastic; neoplastic; pancreatic cancer
    DOI:  https://doi.org/10.1053/j.gastro.2021.07.030
  6. Nat Cancer. 2021 Nov;1 1027-1031
    Future directions in preclinical and translational cancer neuroscience research.
    Neural Influences in Cancer (NIC) International Research Consortium
      Recent advances in cancer neuroscience necessitate the systematic analysis of neural influences in cancer as potential therapeutic targets in oncology. Here, we outline recommendations for future preclinical and translational research in this field.
    DOI:  https://doi.org/10.1038/s43018-020-00146-9
  7. Elife. 2021 Jul 30. pii: e60646. [Epub ahead of print]10
    CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions.
    Veethika Pandey, Alicia Fleming-Martinez, Ligia Bastea, Heike R Doeppler, Jillian Eisenhauer, Tam Le, Brandy Edenfield, Peter Storz.
      The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling, and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor promoting (Ym1+, Fizz+, Arg1+) phenotype, increases fibrosis and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells.
    Keywords:  cancer biology; cell biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.60646
  8. Trends Cancer. 2021 Jul 21. pii: S2405-8033(21)00145-X. [Epub ahead of print]
    Modeling metastasis in mice: a closer look.
    Arianna Giacobbe, Cory Abate-Shen.
      Unraveling the multifaceted cellular and physiological processes associated with metastasis is best achieved by using in vivo models that recapitulate the requisite tumor cell-intrinsic and -extrinsic mechanisms at the organismal level. We discuss the current status of mouse models of metastasis. We consider how mouse models can refine our understanding of the underlying biological and molecular processes that promote metastasis, and we envisage how the application of new technologies will further enhance investigations of metastasis at single-cell resolution in the context of the whole organism. Our view is that investigations based on state-of-the-art mouse models can propel a holistic understanding of the biology of metastasis, which will ultimately lead to the discovery of new therapeutic opportunities.
    Keywords:  genetically engineered mouse models (GEMMs); metastasis; syngeneic models; xenograft models
    DOI:  https://doi.org/10.1016/j.trecan.2021.06.010
  9. Cancer Cell. 2021 Jul 16. pii: S1535-6108(21)00381-0. [Epub ahead of print]
    From bench to bedside: single-cell analysis for cancer immunotherapy.
    Emily F Davis-Marcisak, Atul Deshpande, Genevieve L Stein-O'Brien, Won J Ho, Daniel Laheru, Elizabeth M Jaffee, Elana J Fertig, Luciane T Kagohara.
      Single-cell technologies are emerging as powerful tools for cancer research. These technologies characterize the molecular state of each cell within a tumor, enabling new exploration of tumor heterogeneity, microenvironment cell-type composition, and cell state transitions that affect therapeutic response, particularly in the context of immunotherapy. Analyzing clinical samples has great promise for precision medicine but is technically challenging. Successfully identifying predictors of response requires well-coordinated, multi-disciplinary teams to ensure adequate sample processing for high-quality data generation and computational analysis for data interpretation. Here, we review current approaches to sample processing and computational analysis regarding their application to translational cancer immunotherapy research.
    Keywords:  computational biology; single-cell proteomics; single-cell transcriptomics; spatial proteomics; spatial transcriptomics; translational medicine; tumor immunology
    DOI:  https://doi.org/10.1016/j.ccell.2021.07.004
  10. Autophagy. 2021 Jul 27. 1-2
    All cells are created equal in the sight of autophagy: selective autophagy maintains homeostasis in senescent cells.
    Jaejin Kim, Yeonghyeon Lee, Taerang Jeon, Mi-Sung Kim, Chanhee Kang.
      Macroautophagy/autophagy is a sophisticated quality control program that limits cellular damage and maintains homeostasis, being an essential part of several lifespan-promoting interventions. However, autophagy is also necessary for full establishment of cellular senescence, a causal factor for many age-related diseases and aging. What lies ahead of us to unravel such a paradoxical role of autophagy in senescence is to identify specific targets degraded by autophagy during senescence and determine their importance in the senescence regulatory network. Recently, we developed the "Selective autophagy substrates Identification Platform (SIP)" to advance these goals, providing a rich set of autophagy substrate proteins involved in senescence. Our study demonstrated that selective autophagy coordinates the stress support networks in senescent cells by degrading multiple regulatory components, echoing its homeostatic roles in normal cells. Targeting this type of selective autophagy might provide a unique opportunity to develop non-senescence addiction-based therapeutic strategies for senotherapy by disturbing the homeostatic state of senescent cells.
    Keywords:  Autophagy interactome; cellular senescence; inflammation; oxidative stress; proteostasis; regulated protein stability; selective autophagy; stress support networks
    DOI:  https://doi.org/10.1080/15548627.2021.1953848
  11. Gut. 2021 Jul 30. pii: gutjnl-2020-322874. [Epub ahead of print]
    Discovery and 3D imaging of a novel ΔNp63-expressing basal cell type in human pancreatic ducts with implications in disease.
    Sandrina Martens, Katarina Coolens, Mathias Van Bulck, Tatjana Arsenijevic, Joan Casamitjana, Angel Fernandez Ruiz, Abdessamad El Kaoutari, Jaime Martinez de Villareal, Hediel Madhloum, Farzad Esni, Yves Heremans, Gunter Leuckx, Harry Heimberg, Luc Bouwens, Patrick Jacquemin, Diedert Luc De Paep, Peter In't Veld, Nicky D'Haene, Christelle Bouchart, Nelson Dusetti, Jean-Luc Van Laethem, Wim Waelput, Pierre Lefesvre, Francisco X Real, Meritxell Rovira, Ilse Rooman.
       OBJECTIVE: The aggressive basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) harbours a ΔNp63 (p40) gene expression signature reminiscent of a basal cell type. Distinct from other epithelia with basal tumours, ΔNp63+ basal cells reportedly do not exist in the normal pancreas.
    DESIGN: We evaluated ΔNp63 expression in human pancreas, chronic pancreatitis (CP) and PDAC. We further studied in depth the non-cancerous tissue and developed a three-dimensional (3D) imaging protocol (FLIP-IT, Fluorescence Light sheet microscopic Imaging of Paraffin-embedded or Intact Tissue) to study formalin-fixed paraffin-embedded samples at single cell resolution. Pertinent mouse models and HPDE cells were analysed.
    RESULTS: In normal human pancreas, rare ΔNp63+ cells exist in ducts while their prevalence increases in CP and in a subset of PDAC. In non-cancer tissue, ΔNp63+ cells are atypical KRT19+ duct cells that overall lack SOX9 expression while they do express canonical basal markers and pertain to a niche of cells expressing gastrointestinal stem cell markers. 3D views show that the basal cells anchor on the basal membrane of normal medium to large ducts while in CP they exist in multilayer dome-like structures. In mice, ΔNp63 is not found in adult pancreas nor in selected models of CP or PDAC, but it is induced in organoids from larger Sox9low ducts. In HPDE, ΔNp63 supports a basal cell phenotype at the expense of a classical duct cell differentiation programme.
    CONCLUSION: In larger human pancreatic ducts, basal cells exist. ΔNp63 suppresses duct cell identity. These cells may play an important role in pancreatic disease, including PDAC ontogeny, but are not present in mouse models.
    Keywords:  cancer; development genes; imaging; pancreas; stem cells
    DOI:  https://doi.org/10.1136/gutjnl-2020-322874
  12. EMBO Rep. 2021 Jul 29. e51872
    Calcium signaling induces a partial EMT.
    Robert J Norgard, Jason R Pitarresi, Ravikanth Maddipati, Nicole M Aiello-Couzo, David Balli, Jinyang Li, Taiji Yamazoe, Maximilian D Wengyn, Ian D Millstein, Ian W Folkert, Derick N Rosario-Berrios, Il-Kyu Kim, Jared B Bassett, Riley Payne, Corbett T Berry, Xiaodong Feng, Kathryn Sun, Michele Cioffi, Priyanka Chakraborty, Mohit Kumar Jolly, J Silvio Gutkind, David Lyden, Bruce D Freedman, J Kevin Foskett, Anil K Rustgi, Ben Z Stanger.
      Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of hybrid epithelial-mesenchymal (E-M) states and that cells exhibiting such partial EMT (P-EMT) states have greater metastatic competence than those characterized by either extreme (E or M). We described recently a P-EMT program operating in vivo by which carcinoma cells lose their epithelial state through post-translational programs. Here, we investigate the underlying mechanisms and report that prolonged calcium signaling induces a P-EMT characterized by the internalization of membrane-associated E-cadherin (ECAD) and other epithelial proteins as well as an increase in cellular migration and invasion. Signaling through Gαq-associated G-protein-coupled receptors (GPCRs) recapitulates these effects, which operate through the downstream activation of calmodulin-Camk2b signaling. These results implicate calcium signaling as a trigger for the acquisition of hybrid/partial epithelial-mesenchymal states in carcinoma cells.
    Keywords:  E-cadherin; calcium; cellular plasticity; partial EMT
    DOI:  https://doi.org/10.15252/embr.202051872
  13. Trends Cell Biol. 2021 Jul 22. pii: S0962-8924(21)00140-9. [Epub ahead of print]
    Cell cycle on the crossroad of tumorigenesis and cancer therapy.
    Jing Liu, Yunhua Peng, Wenyi Wei.
      Aberrancy in cell cycle progression is one of the fundamental mechanisms underlying tumorigenesis, making regulators of the cell cycle machinery rational anticancer therapeutic targets. A growing body of evidence indicates that the cell cycle regulatory pathway integrates into other hallmarks of cancer, including metabolism remodeling and immune escape. Thus, therapies against cell cycle machinery components can not only repress the division of cancer cells, but also reverse cancer metabolism and restore cancer immune surveillance. Besides the ongoing effects on the development of small molecule inhibitors (SMIs) of the cell cycle machinery, proteolysis targeting chimeras (PROTACs) have recently been used to target these oncogenic proteins related to cell cycle progression. Here, we discuss the rationale of cell cycle targeting therapies, particularly PROTACs, to more efficiently retard tumorigenesis.
    Keywords:  PROTAC; cancer; cancer immune; cell cycle; degradation; metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2021.07.001
  14. Front Genet. 2021 ;12 691946
    Roles of Phase Separation for Cellular Redox Maintenance.
    Yuichi Saito, Wataru Kimura.
      The oxidation reaction greatly alters characteristics of various cellular components. In exchange for efficient energy production, mitochondrial aerobic respiration substantially increases the risk of excess oxidation of cellular biomolecules such as lipids, proteins, nucleic acids, and numerous small molecules. To maintain a physiologically balanced cellular reduction-oxidation (redox) state, cells utilize a variety of molecular machineries including cellular antioxidants and protein degradation complexes such as the ubiquitin-proteasome system or autophagy. In the past decade, biomolecular liquid-liquid phase separation (LLPS) has emerged as a subject of great interest in the biomedical field, as it plays versatile roles in the maintenance of cellular homeostasis. With regard to redox homeostasis, LLPS arose as a major player in both well-characterized and newly emerging redox pathways. LLPS is involved in direct redox imbalance sensing, signal transduction, and transcriptional regulation. Also, LLPS is at play when cells resist redox imbalance through metabolic switching, translational remodeling, activating the DNA damage response, and segregation of vulnerable lipids and proteins. On the other hand, chronic accumulation of phase-separated molecular condensates such as lipid droplets and amyloid causes neurotoxic outcomes. In this review we enumerate recent progress on understanding how cells utilize LLPS to deal with oxidative stress, especially related to cell survival or pathogenesis, and we discuss future research directions for understanding biological phase separation in cellular redox regulation.
    Keywords:  Nrf2; autophagy; hypoxia; liquid-liquid phase separation; oxidative stress; redox biology
    DOI:  https://doi.org/10.3389/fgene.2021.691946
  15. EJNMMI Res. 2021 Jul 28. 11(1): 70
    [18F]FDG PET/MRI enables early chemotherapy response prediction in pancreatic ductal adenocarcinoma.
    Felix N Harder, Friederike Jungmann, Georgios A Kaissis, Fabian K Lohöfer, Sebastian Ziegelmayer, Daniel Havel, Michael Quante, Maximillian Reichert, Roland M Schmid, Ihsan Ekin Demir, Helmut Friess, Moritz Wildgruber, Jens Siveke, Alexander Muckenhuber, Katja Steiger, Wilko Weichert, Isabel Rauscher, Matthias Eiber, Marcus R Makowski, Rickmer F Braren.
       PURPOSE: In this prospective exploratory study, we evaluated the feasibility of [18F]fluorodeoxyglucose ([18F]FDG) PET/MRI-based chemotherapy response prediction in pancreatic ductal adenocarcinoma at two weeks upon therapy onset.
    MATERIAL AND METHODS: In a mixed cohort, seventeen patients treated with chemotherapy in neoadjuvant or palliative intent were enrolled. All patients were imaged by [18F]FDG PET/MRI before and two weeks after onset of chemotherapy. Response per RECIST1.1 was then assessed at 3 months [18F]FDG PET/MRI-derived parameters (MTV50%, TLG50%, MTV2.5, TLG2.5, SUVmax, SUVpeak, ADCmax, ADCmean and ADCmin) were assessed, using multiple t-test, Man-Whitney-U test and Fisher's exact test for binary features.
    RESULTS: At 72 ± 43 days, twelve patients were classified as responders and five patients as non-responders. An increase in ∆MTV50% and ∆ADC (≥ 20% and 15%, respectively) and a decrease in ∆TLG50% (≤ 20%) at 2 weeks after chemotherapy onset enabled prediction of responders and non-responders, respectively. Parameter combinations (∆TLG50% and ∆ADCmax or ∆MTV50% and ∆ADCmax) further improved discrimination.
    CONCLUSION: Multiparametric [18F]FDG PET/MRI-derived parameters, in particular indicators of a change in tumor glycolysis and cellularity, may enable very early chemotherapy response prediction. Further prospective studies in larger patient cohorts are recommended to their clinical impact.
    Keywords:  Chemotherapy; PDAC; PET/MRI; Response prediction
    DOI:  https://doi.org/10.1186/s13550-021-00808-4
  16. Autophagy. 2021 Jul 25. 1-3
    ATG4s: above and beyond the Atg8-family protein lipidation system.
    Thanh Ngoc Nguyen, Benjamin Scott Padman, Michael Lazarou.
      The sole proteases of the macroautophagy/autophagy machinery, the ATG4s, contribute to autophagosome formation by cleaving Atg8-family protein members (LC3/GABARAPs) which enables Atg8-family protein lipidation and de-lipidation. Our recent work reveals that ATG4s can also promote phagophore growth independently of their protease activity and of Atg8-family proteins. ATG4s and their proximity partners including ARFIP2 and LRBA function to promote trafficking of ATG9A to mitochondria during PINK1-PRKN mitophagy. Through the development of a 3D electron microscopy framework utilizing FIB-SEM and artificial intelligence (termed AIVE: Artificial Intelligence-directed Voxel Extraction), we show that ATG4s promote ER-phagophore contacts during the lipid-transfer phase of autophagosome biogenesis, which requires ATG2B and ATG9A to support phagophore growth. We also discovered that ATG4s are not essential for removal of Atg8-family proteins from autolysosomes, but they can function as deubiquitinase-like enzymes to counteract the conjugation of Atg8-family proteins to other proteins, a process that we have termed ATG8ylation (also known as LC3ylation). These discoveries demonstrate the duality of the ATG4 family in driving autophagosome formation by functioning as both autophagy proteases and trafficking factors, while simultaneously raising questions about the putative roles of ATG8ylation in cell biology.
    Keywords:  ATG4; ATG8; ATG8ylation; PINK1-PRKN mitophagy; Parkinson’s disease; autophagy; de-lipidation; immune disease; mitochondrial dysfunction; ubiquitin-like
    DOI:  https://doi.org/10.1080/15548627.2021.1953263
  17. Cancer Cell Int. 2021 Jul 27. 21(1): 398
    A pancreas tumor derived organoid study: from drug screen to precision medicine.
    Jia Yao, Man Yang, Lawrence Atteh, Pinyan Liu, Yongcui Mao, Wenbo Meng, Xun Li.
      Pancreatic ductal adenocarcinoma (PDAC) one of the deadliest malignant tumor. Despite considerable progress in pancreatic cancer treatment in the past 10 years, PDAC mortality has shown no appreciable change, and systemic therapies for PDAC generally lack efficacy. Thus, developing biomarkers for treatment guidance is urgently required. This review focuses on pancreatic tumor organoids (PTOs), which can mimic the characteristics of the original tumor in vitro. As a powerful tool with several applications, PTOs represent a new strategy for targeted therapy in pancreatic cancer and contribute to the advancement of the field of personalized medicine.
    Keywords:  Drug screen; Pancreas cancer; Pancreas tumor derived organoids (PTOs); Pancreatic ductal adenocarcinoma (PDAC); Precision medicine
    DOI:  https://doi.org/10.1186/s12935-021-02044-1
  18. J Cachexia Sarcopenia Muscle. 2021 Jul 28.
    Anti-cachexia therapy should target metabolism, inflammatory cytokines, and androgens in hormone-independent cancers.
    Charles Paul Lambert.
      
    DOI:  https://doi.org/10.1002/jcsm.12762
  19. JCI Insight. 2021 Jul 27. pii: 132585. [Epub ahead of print]
    Pancreatic specific CHRM3 activation causes pancreatitis in mice.
    Jianhua Wan, Jiale Wang, Larry E Wagner Ii, Oliver H Wang, Fu Gui, Jiaxiang Chen, Xiaohui Zhu, Ashley N Haddock, Brandy H Edenfield, Brian Haight, Debabrata Mukhopadhyay, Ying Wang, David I Yule, Yan Bi, Baoan Ji.
      Hyperstimulation of the cholecystokinin receptor (CCK1R), a Gq-protein coupled receptor (GPCR), in pancreatic acinar cells is commonly used to induce pancreatitis in rodents. Human pancreatic acinar cells lack CCK1R but express cholinergic receptor muscarinic 3 (M3R), another GPCR. To test whether M3R activation is involved in pancreatitis, a mutant M3R was conditionally expressed in pancreatic acinar cells in mice. This mutant receptor loses responsiveness to its native ligand acetylcholine but can be activated by an inert small molecule, clozapine-N-oxide (CNO). Intracellular calcium and amylase were elicited by CNO in pancreatic acinar cells isolated from mutant M3R mice but not WT mice. Similarly, acute pancreatitis (AP) could be induced by a single injection of CNO in the transgenic mice but not WT mice. Compared with the cerulein-induced AP, CNO caused more widespread acinar cell death and inflammation. Furthermore, chronic pancreatitis developed at 4 weeks after 3 episodes of CNO-induced AP. In contrast, in mice with three recurrent episodes of cerulein-included AP, pancreas histology was restored in 4 weeks. Furthermore, the M3R antagonist ameliorated the severity of cerulein-induced AP in WT mice. We conclude that M3R activation can cause the pathogenesis of pancreatitis. This model may provide an alternative approach for pancreatitis research.
    Keywords:  G proteincoupled receptors; Gastroenterology; Inflammation
    DOI:  https://doi.org/10.1172/jci.insight.132585
  20. Nat Rev Cancer. 2021 Jul 29.
    The immunological and metabolic landscape in primary and metastatic liver cancer.
    Xin Li, Pierluigi Ramadori, Dominik Pfister, Marco Seehawer, Lars Zender, Mathias Heikenwalder.
      The liver is the sixth most common site of primary cancer in humans, and generally arises in a background of cirrhosis and inflammation. Moreover, the liver is frequently colonized by metastases from cancers of other organs (particularly the colon) because of its anatomical location and organization, as well as its unique metabolic and immunosuppressive environment. In this Review, we discuss how the hepatic microenvironment adapts to pathologies characterized by chronic inflammation and metabolic alterations. We illustrate how these immunological or metabolic changes alter immunosurveillance and thus hinder or promote the development of primary liver cancer. In addition, we describe how inflammatory and metabolic niches affect the spreading of cancer metastases into or within the liver. Finally, we review the current therapeutic options in this context and the resulting challenges that must be surmounted.
    DOI:  https://doi.org/10.1038/s41568-021-00383-9
  21. FASEB J. 2021 Aug;35(8): e21826
    Caveolin-1 increases glycolysis in pancreatic cancer cells and triggers cachectic states.
    Lijuan Hu, Xiaoqing Xu, Qiuju Li, Xijuan Chen, Xiangfei Yuan, Shuai Qiu, Chuanshan Yao, Dapeng Zhang, Feng Wang.
      In pancreatic cancer, autocrine insulin-like growth factor-1 (IGF-1) and paracrine insulin stimulate both IGF-1 receptor (IGF1R) and insulin receptor (IR) to increase tumor growth and glycolysis. In pancreatic cancer patients, cancer-induced glycolysis increases hepatic gluconeogenesis, skeletal muscle proteolysis, and fat lipolysis and, thereby, causes cancer cachexia. As a protein coexisting with IGF1R and IR, caveolin-1 (cav-1) may be involved in pancreatic cancer-induced cachexia. We undertook the present study to test this hypothesis. Out of wild-type MiaPaCa2 and AsPC1 human pancreatic cancer cell lines, we created their stable sub-lines whose cav-1 expression was diminished with RNA interference or increased with transgene expression. When these cells were studied in vitro, we found that cav-1 regulated IGF1R/IR expression and activation and also regulated cellular glycolysis. We transplanted the different types of MiaPaCa2 cells in growing athymic mice for 8 weeks, using intact athymic mice as tumor-free controls. We found that cav-1 levels in tumor grafts were correlated with expression levels of the enzymes that regulated hepatic gluconeogenesis, skeletal muscle proteolysis, and fat lipolysis in the respective tissues. When the tumors had original or increased cav-1, their carriers' body weight gain was less than the tumor-free reference. When cav-1 was diminished in tumors, the tumor carriers' body weight gain was not changed significantly, compared to the tumor-free reference. In conclusion, cav-1 in pancreatic cancer cells stimulated IGF1R/IR and glycolysis in the cancer cells and triggered cachectic states in the tumor carrier.
    Keywords:  cancer cachexia; caveolin-1; glycolysis; pancreatic cancer
    DOI:  https://doi.org/10.1096/fj.202100121RRR
  22. Nat Rev Cancer. 2021 Jul 30.
    Tissue clearing to examine tumour complexity in three dimensions.
    Jorge Almagro, Hendrik A Messal, May Zaw Thin, Jacco van Rheenen, Axel Behrens.
      The visualization of whole organs and organisms through tissue clearing and fluorescence volumetric imaging has revolutionized the way we look at biological samples. Its application to solid tumours is changing our perception of tumour architecture, revealing signalling networks and cell interactions critical in tumour progression, and provides a powerful new strategy for cancer diagnostics. This Review introduces the latest advances in tissue clearing and three-dimensional imaging, examines the challenges in clearing epithelia - the tissue of origin of most malignancies - and discusses the insights that tissue clearing has brought to cancer research, as well as the prospective applications to experimental and clinical oncology.
    DOI:  https://doi.org/10.1038/s41568-021-00382-w
  23. Trends Genet. 2021 Jul 23. pii: S0168-9525(21)00194-3. [Epub ahead of print]
    HMGs as rheostats of chromosomal structure and cell proliferation.
    Argyris Papantonis.
      High mobility group proteins (HMGs) are the most abundant nuclear proteins next to histones and are robustly expressed across tissues and organs. HMGs can uniquely bend or bind distorted DNA, and are central to such processes as transcription, recombination, and DNA repair. However, their dynamic association with chromatin renders capturing HMGs on chromosomes challenging. Recent work has changed this and now implicates these factors in spatial genome organization. Here, I revisit older and review recent literature to describe how HMGs rewire spatial chromatin interactions to sustain homeostasis or promote cellular aging. I propose a 'rheostat' model to explain how HMG-box proteins (HMGBs), and to some extent HMG A proteins (HMGAs), may control cellular aging and, likely, cancer progression.
    Keywords:  HMG-box; Hi-C; cell proliferation; chromatin folding; senescence; topological domain
    DOI:  https://doi.org/10.1016/j.tig.2021.07.004
  24. Cell Rep. 2021 Jul 27. pii: S2211-1247(21)00858-5. [Epub ahead of print]36(4): 109441
    The Cancer SENESCopedia: A delineation of cancer cell senescence.
    Fleur Jochems, Bram Thijssen, Giulia De Conti, Robin Jansen, Ziva Pogacar, Kelvin Groot, Liqin Wang, Arnout Schepers, Cun Wang, Haojie Jin, Roderick L Beijersbergen, Rodrigo Leite de Oliveira, Lodewyk F A Wessels, René Bernards.
      Cellular senescence is characterized as a stable proliferation arrest that can be triggered by multiple stresses. Most knowledge about senescent cells is obtained from studies in primary cells. However, senescence features may be different in cancer cells, since the pathways that are involved in senescence induction are often deregulated in cancer. We report here a comprehensive analysis of the transcriptome and senolytic responses in a panel of 13 cancer cell lines rendered senescent by two distinct compounds. We show that in cancer cells, the response to senolytic agents and the composition of the senescence-associated secretory phenotype are more influenced by the cell of origin than by the senescence trigger. Using machine learning, we establish the SENCAN gene expression classifier for the detection of senescence in cancer cell samples. The expression profiles and senescence classifier are available as an interactive online Cancer SENESCopedia.
    Keywords:  ABT-263; SASP; SENCAN; SENESCopedia; cancer; cell cycle; gene expression classifier; senescence; senolytics; transcriptome profiling
    DOI:  https://doi.org/10.1016/j.celrep.2021.109441
  25. J Cell Sci. 2021 07 01. pii: jcs252197. [Epub ahead of print]134(13):
    Super-resolution microscopy reveals the arrangement of inner membrane protein complexes in mammalian mitochondria.
    Catherine S Palmer, Jieqiong Lou, Betty Kouskousis, Elvis Pandzic, Alexander J Anderson, Yilin Kang, Elizabeth Hinde, Diana Stojanovski.
      The mitochondrial inner membrane is a protein-rich environment containing large multimeric complexes, including complexes of the mitochondrial electron transport chain, mitochondrial translocases and quality control machineries. Although the inner membrane is highly proteinaceous, with 40-60% of all mitochondrial proteins localised to this compartment, little is known about the spatial distribution and organisation of complexes in this environment. We set out to survey the arrangement of inner membrane complexes using stochastic optical reconstruction microscopy (STORM). We reveal that subunits of the TIM23 complex, TIM23 and TIM44 (also known as TIMM23 and TIMM44, respectively), and the complex IV subunit COXIV, form organised clusters and show properties distinct from the outer membrane protein TOM20 (also known as TOMM20). Density based cluster analysis indicated a bimodal distribution of TIM44 that is distinct from TIM23, suggesting distinct TIM23 subcomplexes. COXIV is arranged in larger clusters that are disrupted upon disruption of complex IV assembly. Thus, STORM super-resolution microscopy is a powerful tool for examining the nanoscale distribution of mitochondrial inner membrane complexes, providing a 'visual' approach for obtaining pivotal information on how mitochondrial complexes exist in a cellular context.
    Keywords:  COXIV; Mitochondria; Mitochondrial complexes; Nanoscopy; Protein import; STORM; TIM23
    DOI:  https://doi.org/10.1242/jcs.252197
  26. Nat Commun. 2021 Jul 30. 12(1): 4651
    The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.
    Nour Ghaddar, Shuo Wang, Bethany Woodvine, Jothilatha Krishnamoorthy, Vincent van Hoef, Cedric Darini, Urszula Kazimierczak, Nicolas Ah-Son, Helmuth Popper, Myriam Johnson, Leah Officer, Ana Teodósio, Massimo Broggini, Koren K Mann, Maria Hatzoglou, Ivan Topisirovic, Ola Larsson, John Le Quesne, Antonis E Koromilas.
      The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.
    DOI:  https://doi.org/10.1038/s41467-021-24661-0
  27. Curr Biol. 2021 Jul 16. pii: S0960-9822(21)00893-9. [Epub ahead of print]
    Sequential oncogenic mutations influence cell competition.
    Koki Kohashi, Yusuke Mori, Rika Narumi, Kei Kozawa, Tomoko Kamasaki, Susumu Ishikawa, Mihoko Kajita, Rei Kobayashi, Yoichiro Tamori, Yasuyuki Fujita.
      At the initial stage of carcinogenesis, newly emerging transformed cells are often eliminated from epithelial layers via cell competition with the surrounding normal cells. For instance, when surrounded by normal cells, oncoprotein RasV12-transformed cells are extruded into the apical lumen of epithelia. During cancer development, multiple oncogenic mutations accumulate within epithelial tissues. However, it remains elusive whether and how cell competition is also involved in this process. In this study, using a mammalian cell culture model system, we have investigated what happens upon the consecutive mutations of Ras and tumor suppressor protein Scribble. When Ras mutation occurs under the Scribble-knockdown background, apical extrusion of Scribble/Ras double-mutant cells is strongly diminished. In addition, at the boundary with Scribble/Ras cells, Scribble-knockdown cells frequently undergo apoptosis and are actively engulfed by the neighboring Scribble/Ras cells. The comparable apoptosis and engulfment phenotypes are also observed in Drosophila epithelial tissues between Scribble/Ras double-mutant and Scribble single-mutant cells. Furthermore, mitochondrial membrane potential is enhanced in Scribble/Ras cells, causing the increased mitochondrial reactive oxygen species (ROS). Suppression of mitochondrial membrane potential or ROS production diminishes apoptosis and engulfment of the surrounding Scribble-knockdown cells, indicating that mitochondrial metabolism plays a key role in the competitive interaction between double- and single-mutant cells. Moreover, mTOR (mechanistic target of rapamycin kinase) acts downstream of these processes. These results imply that sequential oncogenic mutations can profoundly influence cell competition, a transition from loser to winner. Further studies would open new avenues for cell competition-based cancer treatment, thereby blocking clonal expansion of more malignant populations within tumors.
    Keywords:  ROS; RasV12; Scribble; apoptosis; cell competition; engulfment; entosis; mTOR; mitochondria; sequential mutations
    DOI:  https://doi.org/10.1016/j.cub.2021.06.064
  28. J Biol Chem. 2021 Jul 27. pii: S0021-9258(21)00817-6. [Epub ahead of print] 101015
    TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells.
    Gyula Diszházi, Zsuzsanna É Magyar, Erika Lisztes, Edit Tóth-Molnár, Péter P Nánási, Rudi Vennekens, Balázs I Tóth, János Almássy.
      TRPM4 is a Ca2+-activated nonselective cation channel that mediates membrane depolarization. Although, a current with the hallmarks of a TRPM4-mediated current has been previously reported in pancreatic acinar cells (PAC), the role of TRPM4 in the regulation of acinar cell function has not yet been explored. In the present study, we identify this TRPM4 current and describe its role in context of Ca2+ signaling of PACs using pharmacological tools and TRPM4-deficient mice. We found a significant Ca2+-activated cation current in PACs that was sensitive to the TRPM4 inhibitors 9-phenanthrol and CBA (4-Chloro-2-[[2-(2-chlorophenoxy)acetyl]amino]benzoic acid). We demonstrated that the CBA-sensitive current was responsible for a Ca2+-dependent depolarization of PACs from a resting membrane potential of -44.4 ± 2.9 to -27.7 ± 3 mV. Furthermore, we showed that Ca2+ influx was higher in the TRPM4 KO- and CBA-treated PACs than in control cells. As hormone induced repetitive Ca2+ transients partially rely on Ca2+ influx in PACs, the role of TRPM4 was also assessed on Ca2+ oscillations elicited by physiologically relevant concentrations of the cholecystokinin analogue cerulein. These data show that the amplitude of Ca2+ signals were significantly higher in TRPM4 KO than in control PACs. Our results suggest that PACs are depolarized by TRPM4 currents to an extent that results in a significant reduction of the inward driving force for Ca2+. In conclusion, TRPM4 links intracellular Ca2+ signaling to membrane potential as a negative feedback regulator of Ca2+ entry in PACs.
    Keywords:  TRPM4; acinar cells; calcium entry; calcium imaging; calcium signaling; ion channel; pancreas; patch clamp; physiology; transient receptor potential channels (TRP channels)
    DOI:  https://doi.org/10.1016/j.jbc.2021.101015
  29. J Clin Invest. 2021 Jul 29. pii: 140521. [Epub ahead of print]
    Tanycytic networks mediate energy balance by feeding lactate to glucose-insensitive POMC neurons.
    Tori Lhomme, Jerome Clasadonte, Monica Imbernon, Daniela Fernandois, Florent Sauve, Emilie Caron, Natalia Lima, Violeta Heras, Ines Martinez-Corral, Helge Müller-Fielitz, S Rasika, Markus Schwaninger, Ruben Nogueiras, Vincent Prevot.
      Hypothalamic glucose sensing enables an organism to match energy expenditure and food intake to circulating levels of glucose, the main energy source of the brain. Here, we established that tanycytes of the hypothalamic arcuate nucleus, specialized glia that line the wall of the third ventricle, convert brain glucose supplies into lactate that they transmit through monocarboxylate transporters to arcuate proopiomelanocortin neurons, which integrate this signal to drive their activity and to adapt the metabolic response to meet physiological demands. Furthermore, this transmission required the formation of extensive Connexin-43 gap-junction-mediated metabolic networks by arcuate tanycytes. Selectively suppressing either tanycytic monocarboxylate transporters or gap junctions resulted in altered feeding behavior and energy metabolism. Tanycytic intercellular communication and lactate production are thus integral to the mechanism by which hypothalamic neurons that regulate energy and glucose homeostasis efficiently perceive alterations in systemic glucose levels as a function of the physiological state of the organism.
    Keywords:  Glucose metabolism; Homeostasis; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1172/JCI140521
  30. Science. 2021 07 30. 373(6554): 486-487
    Control of condensates dictates nucleolar architecture.
    Tomohiro Yamazaki, Tetsuro Hirose.
      
    DOI:  https://doi.org/10.1126/science.abj8350
  31. Aging (Albany NY). 2021 Jul 28. 13(undefined):
    Features of age-related response to sleep deprivation: in vivo experimental studies.
    Maria Novozhilova, Tatiana Mishchenko, Elena Kondakova, Tatiana Lavrova, Maria Gavrish, Svetlana Aferova, Claudio Franceschi, Maria Vedunova.
      Insomnia is currently considered one of the potential triggers of accelerated aging. The frequency of registered sleep-wake cycle complaints increases with age and correlates with the quality of life of elderly people. Nevertheless, whether insomnia is actually an age-associated process or whether it acts as an independent stress-factor that activates pathological processes, remains controversial. In this study, we analyzed the effects of long-term sleep deprivation modeling on the locomotor and orienting-exploratory activity, spatial learning abilities and working memory of C57BL/6 female mice of different ages. We also evaluated the modeled stress influence on morphological changes in brain tissue, the functional activity of the mitochondrial apparatus of nerve cells, and the level of DNA methylation and mRNA expression levels of the transcription factor HIF-1α (Hif1) and age-associated molecular marker PLIN2. Our findings point to the age-related adaptive capacity of female mice to the long-term sleep deprivation influence. For young (1.5 months) mice, the modeled sleep deprivation acts as a stress factor leading to weight loss against the background of increased food intake, the activation of animals' locomotor and exploratory activity, their mnestic functions, and molecular and cellular adaptive processes ensuring animal resistance both to stress and risk of accelerated aging development. Sleep deprivation in adult (7-9 months) mice is accompanied by an increase in body weight against the background of active food intake, increased locomotor and exploratory activity, gross disturbances in mnestic functions, and decreased adaptive capacity of brain cells, that potentially increasing the risk of pathological reactions and neurodegenerative processes.
    Keywords:  DNA methylation; PLIN2; aging; learning ability; sleep deprivation
    DOI:  https://doi.org/10.18632/aging.203372
  32. Methods Cell Biol. 2021 ;pii: S0091-679X(20)30193-X. [Epub ahead of print]165 153-161
    Monitoring selective autophagy of mitochondria using super-resolution microscopy.
    Ziyue Li, Nicholas T Ktistakis.
      Selective elimination of damaged mitochondria via macroautophagy (mitophagy) is a conserved cellular process that plays an important role in organismal health. In recent years mitophagy has been studied in parallel to the more general, non-selective autophagy pathway induced in response to amino acid starvation with important similarities and differences noted between the two. The elaborate sequence of membrane rearrangements that give rise to autophagosomes in the non-selective pathway have their counterpart in mitophagy, but with the addition of other factors, such as a ubiquitin mark and mitophagy receptors, which mediate cargo recognition. In some types of mitophagy such as the one induced by ivermectin, the forming autophagosomal structure contains six different elements: the targeted mitochondrial fragment, a section of endoplasmic reticulum that provides a cradle, a ubiquitin layer, the mitophagy receptors and the early and late autophagosomal proteins/membranes. Super-resolution microscopy is ideally suited to investigate the spatial relationships between these elements that converge together but retain some distinctive localization, and we provide here a general protocol that can be used for mammalian cells.
    Keywords:  Autophagy; Endoplasmic reticulum; Ivermectin; Mitochondria; Mitophagy; Structured illumination microscopy
    DOI:  https://doi.org/10.1016/bs.mcb.2020.10.010
  33. J Exp Clin Cancer Res. 2021 Jul 29. 40(1): 243
    Cellular senescence or stemness: hypoxia flips the coin.
    Daniel Otero-Albiol, Amancio Carnero.
      Cellular senescence is a complex physiological state whose main feature is proliferative arrest. Cellular senescence can be considered the reverse of cell immortalization and continuous tumor growth. However, cellular senescence has many physiological functions beyond being a putative tumor suppressive trait. It remains unknown whether low levels of oxygen or hypoxia, which is a feature of every tissue in the organism, modulate cellular senescence, altering its capacity to suppress the limitation of proliferation. It has been observed that the lifespan of mammalian primary cells is increased under low oxygen conditions. Additionally, hypoxia promotes self-renewal and pluripotency maintenance in adult and embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and cancer stem cells (CSCs). In this study, we discuss the role of hypoxia facilitating senescence bypass during malignant transformation and acquisition of stemness properties, which all contribute to tumor development and cancer disease aggressiveness.
    Keywords:  cancer; cellular senescence; dedifferentiation; hypoxia; immortalization; oxygen; stemness
    DOI:  https://doi.org/10.1186/s13046-021-02035-0
  34. Methods Mol Biol. 2021 ;2350 31-41
    Multiplexed Imaging of Posttranslational Modifications of Endogenous Proteins in Live Cells.
    Yuko Sato, Hiroshi Kimura.
      Posttranslational histone modifications are associated with the regulation of genome function. Some modifications are quite stable to maintain epigenome states of chromatin, and others can exhibit dynamic changes in response to internal and external stimuli. To track the local and global changes in histone modifications, multiplexed imaging in living cells is beneficial. Among live cell probes for detecting histone modifications, genetically encoded modification-specific intracellular antibodies, or mintbodies, are convenient and suitable tools for this purpose. We here describe the mintbody-based methods to monitor the changes in histone modification levels induced by histone methyltransferase and deacetylase inhibitors. By measuring the nuclear to cytoplasmic intensity ratios of mintbodies in living cells, changes in histone H4 lysine 20 methylation states and the increase in histone H3 acetylation were detected.
    Keywords:  Histone modifications; Live-cell imaging; Modification-specific intracellular antibody
    DOI:  https://doi.org/10.1007/978-1-0716-1593-5_3
  35. Elife. 2021 Jul 27. pii: e66643. [Epub ahead of print]10
    T cell stiffness is enhanced upon formation of immunological synapse.
    Philipp Jung, Xiangda Zhou, Sandra Iden, Markus Bischoff, Bin Qu.
      T cells are activated by target cells via an intimate contact, termed immunological synapse (IS). Cellular mechanical properties, especially stiffness, are essential to regulate cell functions. However, T cell stiffness at a subcellular level at the IS still remains largely elusive. In this work, we established an atomic force microscopy (AFM)-based elasticity mapping method on whole T cells to obtain an overview of the stiffness with a resolution of ~ 60 nm. Using primary human CD4+ T cells, we show that when T cells form IS with stimulating antibody-coated surfaces, the lamellipodia are stiffer than the cell body. Upon IS formation, T cell stiffness is enhanced both at the lamellipodia and on the cell body. Chelation of intracellular Ca2+ abolishes IS-induced stiffening at the lamellipodia but has no influence on cell body-stiffening, suggesting different regulatory mechanisms of IS-induced stiffening at the lamellipodia and the cell body.
    Keywords:  human; immunology; inflammation; physics of living systems
    DOI:  https://doi.org/10.7554/eLife.66643
  36. Nat Rev Cancer. 2021 Jul 27.
    Mutational signatures: emerging concepts, caveats and clinical applications.
    Gene Koh, Andrea Degasperi, Xueqing Zou, Sophie Momen, Serena Nik-Zainal.
      Whole-genome sequencing has brought the cancer genomics community into new territory. Thanks to the sheer power provided by the thousands of mutations present in each patient's cancer, we have been able to discern generic patterns of mutations, termed 'mutational signatures', that arise during tumorigenesis. These mutational signatures provide new insights into the causes of individual cancers, revealing both endogenous and exogenous factors that have influenced cancer development. This Review brings readers up to date in a field that is expanding in computational, experimental and clinical directions. We focus on recent conceptual advances, underscoring some of the caveats associated with using the mutational signature frameworks and highlighting the latest experimental insights. We conclude by bringing attention to areas that are likely to see advancements in clinical applications.
    DOI:  https://doi.org/10.1038/s41568-021-00377-7
  37. Curr Opin Struct Biol. 2021 Jul 23. pii: S0959-440X(21)00092-0. [Epub ahead of print]71 164-170
    The dynamic nature of the K-Ras/calmodulin complex can be altered by oncogenic mutations.
    Hazem Abdelkarim, Nicholas Leschinsky, Hyunbum Jang, Avik Banerjee, Ruth Nussinov, Vadim Gaponenko.
      Oncogenic mutant K-Ras promotes cancer cell proliferation, migration, invasion, and survival by assembling signaling complexes. To date, the functional and structural roles of K-Ras mutations within these complexes are incompletely understood despite their mechanistic and therapeutic significance. Here, we review recent advances in understanding specific binding between K-Ras and the calcium sensor calmodulin. This interaction positively and negatively regulates diverse functions of K-Ras in cancer, suggesting flexibility in K-Ras/calmodulin complex formation. Also, structural data suggest that oncogenic K-Ras likely samples several conformational states, influencing its distinct assemblies with calmodulin and with other proteins. Understanding how K-Ras interacts with calmodulin and with other partners is essential to discovering novel inhibitors of K-Ras in cancer.
    DOI:  https://doi.org/10.1016/j.sbi.2021.06.008
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