bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2021–08–15
thirty papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis.
  2. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.
  3. Histone Methylation Connects DNA Repair to Metabolism in Cancer Cells.
  4. Cycling cancer persister cells arise from lineages with distinct programs.
  5. Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to ex vivo culture stress and aging.
  6. Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin.
  7. Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer.
  8. A composite DNA element that functions as a maintainer required for epigenetic inheritance of heterochromatin.
  9. Liquid-liquid phase separation: a principal organizer of the cell's biochemical activity architecture.
  10. Cell competition in intratumoral and tumor microenvironment interactions.
  11. Large organellar changes occur during mild heat shock in yeast.
  12. The pathogenesis of mesothelioma is driven by a dysregulated translatome.
  13. Lipid droplets form a network interconnected by the endoplasmic reticulum through which their proteins equilibrate.
  14. Metabolic orchestration of the wound healing response.
  15. Extracellular matrix-based cancer targeting.
  16. TRIM44 links the UPS to SQSTM1/p62-dependent aggrephagy and removing misfolded proteins.
  17. Spatiotemporal coordination of transcription preinitiation complex assembly in live cells.
  18. The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.
  19. Targeting Aging: Lessons Learned From Immunometabolism and Cellular Senescence.
  20. A phase II study of FOLFIRINOX with primary prophylactic pegfilgrastim for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.
  21. Putative homeostatic role of cancer driver mutations.
  22. The promise and peril of KRAS G12C inhibitors.
  23. A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies.
  24. The Potential of Calorie Restriction and Calorie Restriction Mimetics in Delaying Aging: Focus on Experimental Models.
  25. The lysosome as a master regulator of iron metabolism.
  26. Molecular phenotyping reveals the identity of Barrett's esophagus and its malignant transition.
  27. Modulation of cell physiology under hypoxia in pancreatic cancer.
  28. Next-generation cancer organoids.
  29. Delineating the lipidated Atg8 structure for unveiling its hidden activity in autophagy.
  30. Phase Separation in RNA Biology.
  1. Nat Commun. 2021 08 11. 12(1): 4860
    GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis.
    Daniel M Kremer, Barbara S Nelson, Lin Lin, Emily L Yarosz, Christopher J Halbrook, Samuel A Kerk, Peter Sajjakulnukit, Amy Myers, Galloway Thurston, Sean W Hou, Eileen S Carpenter, Anthony C Andren, Zeribe C Nwosu, Nicholas Cusmano, Stephanie Wisner, Nneka E Mbah, Mengrou Shan, Nupur K Das, Brian Magnuson, Andrew C Little, Milan R Savani, Johanna Ramos, Tina Gao, Stephen A Sastra, Carmine F Palermo, Michael A Badgley, Li Zhang, John M Asara, Samuel K McBrayer, Marina Pasca di Magliano, Howard C Crawford, Yatrik M Shah, Kenneth P Olive, Costas A Lyssiotis.
      Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.
    DOI:  https://doi.org/10.1038/s41467-021-24859-2
  2. Cell. 2021 Aug 06. pii: S0092-8674(21)00879-5. [Epub ahead of print]
    Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.
    Kazuhiro Koikawa, Shin Kibe, Futoshi Suizu, Nobufumi Sekino, Nami Kim, Theresa D Manz, Benika J Pinch, Dipikaa Akshinthala, Ana Verma, Giorgio Gaglia, Yutaka Nezu, Shizhong Ke, Chenxi Qiu, Kenoki Ohuchida, Yoshinao Oda, Tae Ho Lee, Babara Wegiel, John G Clohessy, Nir London, Sandro Santagata, Gerburg M Wulf, Manuel Hidalgo, Senthil K Muthuswamy, Masafumi Nakamura, Nathanael S Gray, Xiao Zhen Zhou, Kun Ping Lu.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.
    Keywords:  Pin1; cancer immune evasion; cancer-associated fibroblasts; chemotherapy; combination therapy; immuni checkpoint therapy; pancreatic cancer; targeted therapy; tumor immune microenvironment; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2021.07.020
  3. Cancer Discov. 2020 Aug;10(8): OF7
    Histone Methylation Connects DNA Repair to Metabolism in Cancer Cells.
      Metabolites produced in cancer cells interfered with resolution of DNA double-strand breaks.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-089
  4. Nature. 2021 Aug 11.
    Cycling cancer persister cells arise from lineages with distinct programs.
    Yaara Oren, Michael Tsabar, Michael S Cuoco, Liat Amir-Zilberstein, Heidie F Cabanos, Jan-Christian Hütter, Bomiao Hu, Pratiksha I Thakore, Marcin Tabaka, Charles P Fulco, William Colgan, Brandon M Cuevas, Sara A Hurvitz, Dennis J Slamon, Amy Deik, Kerry A Pierce, Clary Clish, Aaron N Hata, Elma Zaganjor, Galit Lahav, Katerina Politi, Joan S Brugge, Aviv Regev.
      Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure1, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment2. Although most cancer persisters remain arrested in the presence of the drug, a rare subset can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drugs. To study this rare, transiently resistant, proliferative persister population, we developed Watermelon, a high-complexity expressed barcode lentiviral library for simultaneous tracing of each cell's clonal origin and proliferative and transcriptional states. Here we show that cycling and non-cycling persisters arise from different cell lineages with distinct transcriptional and metabolic programs. Upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation are associated with persister proliferative capacity across multiple cancer types. Impeding oxidative stress or metabolic reprogramming alters the fraction of cycling persisters. In human tumours, programs associated with cycling persisters are induced in minimal residual disease in response to multiple targeted therapies. The Watermelon system enabled the identification of rare persister lineages that are preferentially poised to proliferate under drug pressure, thus exposing new vulnerabilities that can be targeted to delay or even prevent disease recurrence.
    DOI:  https://doi.org/10.1038/s41586-021-03796-6
  5. Cell Stem Cell. 2021 Aug 06. pii: S1934-5909(21)00294-0. [Epub ahead of print]
    Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to ex vivo culture stress and aging.
    Miriama Kruta, Mary Jean Sunshine, Bernadette A Chua, Yunpeng Fu, Ashu Chawla, Christopher H Dillingham, Lorena Hidalgo San Jose, Bijou De Jong, Fanny J Zhou, Robert A J Signer.
      Maintaining proteostasis is key to resisting stress and promoting healthy aging. Proteostasis is necessary to preserve stem cell function, but little is known about the mechanisms that regulate proteostasis during stress in stem cells, and whether disruptions of proteostasis contribute to stem cell aging is largely unexplored. We determined that ex-vivo-cultured mouse and human hematopoietic stem cells (HSCs) rapidly increase protein synthesis. This challenge to HSC proteostasis was associated with nuclear accumulation of Hsf1, and deletion of Hsf1 impaired HSC maintenance ex vivo. Strikingly, supplementing cultures with small molecules that enhance Hsf1 activation partially suppressed protein synthesis, rebalanced proteostasis, and supported retention of HSC serial reconstituting activity. Although Hsf1 was dispensable for young adult HSCs in vivo, Hsf1 deficiency increased protein synthesis and impaired the reconstituting activity of middle-aged HSCs. Hsf1 thus promotes proteostasis and the regenerative activity of HSCs in response to culture stress and aging.
    Keywords:  Hsf1; aging; heat shock response; hematopoiesis; hematopoietic stem cell; protein synthesis; proteostasis; stem cell; stress; translation
    DOI:  https://doi.org/10.1016/j.stem.2021.07.009
  6. Cell Metab. 2021 Aug 04. pii: S1550-4131(21)00363-6. [Epub ahead of print]
    Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin.
    Jesper Bäckdahl, Lovisa Franzén, Lucas Massier, Qian Li, Jutta Jalkanen, Hui Gao, Alma Andersson, Nayanika Bhalla, Anders Thorell, Mikael Rydén, Patrik L Ståhl, Niklas Mejhert.
      The contribution of cellular heterogeneity and architecture to white adipose tissue (WAT) function is poorly understood. Herein, we combined spatially resolved transcriptional profiling with single-cell RNA sequencing and image analyses to map human WAT composition and structure. This identified 18 cell classes with unique propensities to form spatially organized homo- and heterotypic clusters. Of these, three constituted mature adipocytes that were similar in size, but distinct in their spatial arrangements and transcriptional profiles. Based on marker genes, we termed these AdipoLEP, AdipoPLIN, and AdipoSAA. We confirmed, in independent datasets, that their respective gene profiles associated differently with both adipocyte and whole-body insulin sensitivity. Corroborating our observations, insulin stimulation in vivo by hyperinsulinemic-euglycemic clamp showed that only AdipoPLIN displayed a transcriptional response to insulin. Altogether, by mining this multimodal resource we identify that human WAT is composed of three classes of mature adipocytes, only one of which is insulin responsive.
    Keywords:  insulin sensitivity; obesity; single-cell RNA sequencing; spatial transcriptomics; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.018
  7. EMBO Mol Med. 2021 Aug 08. e13193
    Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer.
    Zhang Yang, Shun-Qing Liang, Maria Saliakoura, Haitang Yang, Eric Vassella, Georgia Konstantinidou, Mario Tschan, Balazs Hegedüs, Liang Zhao, Yanyun Gao, Duo Xu, Haibin Deng, Thomas M Marti, Gregor J Kocher, Wenxiang Wang, Ralph A Schmid, Ren-Wang Peng.
      KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS-driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS-mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti-proliferative effects and cell death in KRAS-mutant lung and pancreatic but not colon nor KRAS wild-type cancer cells. Mechanistically, co-targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress-activated c-Jun N-terminal kinase (JNK)/p38 pathway and E2F1-induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS-mutant patient-derived xenografts and a genetically engineered mouse model of Kras-induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS-mutant cancer.
    Keywords:  KRAS-mutant cancer; autophagy; fibroblast growth factor receptor 1; polo-like kinase 1; synthetic lethal vulnerability
    DOI:  https://doi.org/10.15252/emmm.202013193
  8. Mol Cell. 2021 Aug 03. pii: S1097-2765(21)00586-4. [Epub ahead of print]
    A composite DNA element that functions as a maintainer required for epigenetic inheritance of heterochromatin.
    Xiaoyi Wang, Joao A Paulo, Xue Li, Haining Zhou, Juntao Yu, Steven P Gygi, Danesh Moazed.
      Epigenetic inheritance of heterochromatin requires DNA-sequence-independent propagation mechanisms, coupling to RNAi, or input from DNA sequence, but how DNA contributes to inheritance is not understood. Here, we identify a DNA element (termed "maintainer") that is sufficient for epigenetic inheritance of pre-existing histone H3 lysine 9 methylation (H3K9me) and heterochromatin in Schizosaccharomyces pombe but cannot establish de novo gene silencing in wild-type cells. This maintainer is a composite DNA element with binding sites for the Atf1/Pcr1 and Deb1 transcription factors and the origin recognition complex (ORC), located within a 130-bp region, and can be converted to a silencer in cells with lower rates of H3K9me turnover, suggesting that it participates in recruiting the H3K9 methyltransferase Clr4/Suv39h. These results suggest that, in the absence of RNAi, histone H3K9me is only heritable when it can collaborate with maintainer-associated DNA-binding proteins that help recruit the enzyme responsible for its epigenetic deposition.
    Keywords:  Atf1; Clr4; Deb1; H3K9me; ORC; Pcr1; Suv39h; epigenetic inheritance; heterochromatin; maintainer
    DOI:  https://doi.org/10.1016/j.molcel.2021.07.017
  9. Trends Pharmacol Sci. 2021 Aug 06. pii: S0165-6147(21)00138-3. [Epub ahead of print]
    Liquid-liquid phase separation: a principal organizer of the cell's biochemical activity architecture.
    Jason Z Zhang, Sohum Mehta, Jin Zhang.
      Numerous processes occur simultaneously in the cell both for normal function and in response to changes in the environment. The ability of cells to segregate biochemical reactions into separate compartments is essential to ensure specificity and efficiency in cellular processes. The discovery of liquid-liquid phase separation as a mechanism of compartmentalization has revised our thinking regarding the intracellular organization of molecular pathways such as signal transduction. Here, we highlight recent studies that advance our understanding of how phase separation impacts the organization of biochemical processes, with a particular focus on the tools used to study the functional impact of phase separation. In addition, we offer some of our perspectives on the pathological consequences of dysregulated phase separation in biochemical pathways.
    DOI:  https://doi.org/10.1016/j.tips.2021.07.003
  10. EMBO J. 2021 Aug 09. e107271
    Cell competition in intratumoral and tumor microenvironment interactions.
    Taylor M Parker, Kartik Gupta, António M Palma, Michail Yekelchyk, Paul B Fisher, Steven R Grossman, Kyoung Jae Won, Esha Madan, Eduardo Moreno, Rajan Gogna.
      Tumors are complex cellular and acellular environments within which cancer clones are under continuous selection pressures. Cancer cells are in a permanent mode of interaction and competition with each other as well as with the immediate microenvironment. In the course of these competitive interactions, cells share information regarding their general state of fitness, with less-fit cells being typically eliminated via apoptosis at the hands of those cells with greater cellular fitness. Competitive interactions involving exchange of cell fitness information have implications for tumor growth, metastasis, and therapy outcomes. Recent research has highlighted sophisticated pathways such as Flower, Hippo, Myc, and p53 signaling, which are employed by cancer cells and the surrounding microenvironment cells to achieve their evolutionary goals by means of cell competition mechanisms. In this review, we discuss these recent findings and explain their importance and role in evolution, growth, and treatment of cancer. We further consider potential physiological conditions, such as hypoxia and chemotherapy, that can function as selective pressures under which cell competition mechanisms may evolve differently or synergistically to confer oncogenic advantages to cancer.
    Keywords:  cancer; cell competition; chemotherapy; clonal selection; tumor heterogeneity
    DOI:  https://doi.org/10.15252/embj.2020107271
  11. J Cell Sci. 2022 Mar 01. pii: jcs258325. [Epub ahead of print]135(5):
    Large organellar changes occur during mild heat shock in yeast.
    Katharina S Keuenhof, Lisa Larsson Berglund, Sandra Malmgren Hill, Kara L Schneider, Per O Widlund, Thomas Nyström, Johanna L Höög.
      When the temperature is increased, the heat-shock response is activated to protect the cellular environment. The transcriptomics and proteomics of this process are intensively studied, while information about how the cell responds structurally to heat stress is mostly lacking. Here, Saccharomyces cerevisiae were subjected to a mild continuous heat shock (38°C) and intermittently cryo-immobilised for electron microscopy. Through measuring changes in all distinguishable organelle numbers, sizes and morphologies in over 2100 electron micrographs, a major restructuring of the internal architecture of the cell during the progressive heat shock was revealed. The cell grew larger but most organelles within it expanded even more, shrinking the volume of the cytoplasm. Organelles responded to heat shock at different times, both in terms of size and number, and adaptations of the morphology of some organelles (such as the vacuole) were observed. Multivesicular bodies grew by almost 70%, indicating a previously unknown involvement in the heat-shock response. A previously undescribed electron-translucent structure accumulated close to the plasma membrane. This all-encompassing approach provides a detailed chronological progression of organelle adaptation throughout the cellular heat-stress response.
    Keywords:  Budding yeast; Electron microscopy; Heat shock; Organelles; Ultrastructure
    DOI:  https://doi.org/10.1242/jcs.258325
  12. Nat Commun. 2021 Aug 13. 12(1): 4920
    The pathogenesis of mesothelioma is driven by a dysregulated translatome.
    Stefano Grosso, Alberto Marini, Katarina Gyuraszova, Johan Vande Voorde, Aristeidis Sfakianos, Gavin D Garland, Angela Rubio Tenor, Ryan Mordue, Tanya Chernova, Nobu Morone, Marco Sereno, Claire P Smith, Leah Officer, Pooyeh Farahmand, Claire Rooney, David Sumpton, Madhumita Das, Ana Teodósio, Catherine Ficken, Maria Guerra Martin, Ruth V Spriggs, Xiao-Ming Sun, Martin Bushell, Owen J Sansom, Daniel Murphy, Marion MacFarlane, John P C Le Quesne, Anne E Willis.
      Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no 'druggable' driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease.
    DOI:  https://doi.org/10.1038/s41467-021-25173-7
  13. J Cell Sci. 2022 Mar 01. pii: jcs258819. [Epub ahead of print]135(5):
    Lipid droplets form a network interconnected by the endoplasmic reticulum through which their proteins equilibrate.
    Stéphanie Cottier, Roger Schneiter.
      Lipid droplets (LDs) are globular intracellular structures dedicated to the storage of neutral lipids. They are closely associated with the endoplasmic reticulum (ER) and are delineated by a monolayer of phospholipids that is continuous with the cytoplasmic leaflet of the ER membrane. LDs contain a specific set of proteins, but how these proteins are targeted to the LD surface is not fully understood. Here, we devised a yeast mating-based microscopic readout to monitor the transfer of LD proteins upon zygote formation. The results of this analysis indicate that ER fusion between mating partners is required for transfer of LD proteins and that this transfer is continuous, bidirectional and affects most LDs simultaneously. These observations suggest that LDs do not fuse upon mating of yeast cells, but that they form a network that is interconnected through the ER membrane. Consistent with this, ER-localized LD proteins rapidly move onto LDs of a mating partner and this protein transfer is affected by seipin, a protein important for proper LD biogenesis and the functional connection of LDs with the ER membrane.
    Keywords:   Saccharomyces cerevisiae ; Endoplasmic reticulum; Lipid droplets; Mating; Membrane fusion; Protein targeting; Seipin; Steryl esters; Triacylglycerol
    DOI:  https://doi.org/10.1242/jcs.258819
  14. Cell Metab. 2021 Aug 09. pii: S1550-4131(21)00362-4. [Epub ahead of print]
    Metabolic orchestration of the wound healing response.
    Sabine A Eming, Peter J Murray, Edward J Pearce.
      Wound healing requires cooperation between different cell types, among which macrophages play a central role. In particular, inflammatory macrophages are engaged in the initial response to wounding, and alternatively activated macrophages are essential for wound closure and the resolution of tissue repair. The links between temporal activation-induced changes in the metabolism of such macrophages and the influence this has on their functional states, along with the realization that metabolites play both intrinsic and extrinsic roles in the cells that produce them, has focused attention on the metabolism of wound healing. Here, we discuss macrophage metabolism during distinct stages of normal healing and its related pathologic processes, such as during cancer and fibrosis. Further, we frame these insights in a broader context of the current understanding of macrophage metabolic reprogramming linked to cellular activation and function. Finally, we discuss parallels between the metabolism of macrophages and fibroblasts, the latter being a key stromal cell type in wound healing, and consider the importance of the metabolic interplay between different cell types in the wound microenvironment.
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.017
  15. Trends Mol Med. 2021 Aug 10. pii: S1471-4914(21)00190-8. [Epub ahead of print]
    Extracellular matrix-based cancer targeting.
    Nikos K Karamanos, Zoi Piperigkou, Alberto Passi, Martin Götte, Patricia Rousselle, Israel Vlodavsky.
      Tumor extracellular matrix (ECM) operates in a coordinated mode with cancer and stroma cells to evoke the multistep process of metastatic potential. The remodeled tumor-associated matrix provides a point for direct or complementary therapeutic targeting. Here, we cover and critically address the importance of ECM networks and their macromolecules in cancer. We focus on the roles of key structural and functional ECM components, and their degradation enzymes and extracellular vesicles, aiming at improving our understanding of the mechanisms contributing to tumor initiation, growth, and dissemination, and discuss potential new approaches for ECM-based therapeutic targeting and diagnosis.
    Keywords:  cancer; collagen; extracellular matrix; hyaluronan; matrix remodeling enzymes; proteoglycans
    DOI:  https://doi.org/10.1016/j.molmed.2021.07.009
  16. Autophagy. 2021 Aug 12. 1-16
    TRIM44 links the UPS to SQSTM1/p62-dependent aggrephagy and removing misfolded proteins.
    Lin Lyu, Zheng Chen, Nami McCarty.
      Until recently, the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy were considered to be two independent systems that target proteins for degradation by proteasomes or via lysosomes, respectively. Here, we report that TRIM44 (tripartite motif containing 44) is a novel link that connects the UPS system with the autophagy degradation pathway. Suppressing the UPS degradation pathway leads to TRIM44 upregulation, which further promotes aggregated protein clearance through the binding of K48 ubiquitin chains on proteins. TRIM44 expression activates autophagy via promoting SQSTM1/p62 oligomerization, which rapidly increases the rate of aggregate protein removal. Overall, our data reveal that TRIM44 is a newly identified link between the UPS system and the autophagy pathway. Delineating the cross-talk between these two degradation pathways may reveal new mechanisms of targeting aggregate-prone diseases, such as cancer and neurodegenerative disease.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; ATG5: autophagy related 5; BB: B-box domain; BECN1: beclin1; BM: bone marrow; CC: coiled-coil domain; CFTR: cystic fibrosis transmembrane conductance regulator; CON: control; CQ: chloroquine; DOX: doxycycline; DSP: dithiobis(succinimidly propionate); ER: endoplasmic reticulum; FI: fluorescence intensity; FL: full length; HIF1A/HIF-1#x3B1;: hypoxia inducible factor 1 subunit alpha; HSC: hematopoietic stem cells; HTT: huntingtin; KD: knockdown; KD-CON: knockdown construct control; MM: multiple myeloma; MTOR: mechanistic target of rapamycin kinase; NP-40: nonidet P-40; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; OE: overexpression; OE-CON: overexpression construct control; PARP: poly (ADP-ribose) polymerase; SDS: sodium dodecyl sulfate; SQSTM1/p62: sequestosome 1; Tet-on: tetracycline; TRIM44: tripartite motif containing 44; UPS: ubiquitin-proteasome system; ZF: zinc-finger.
    Keywords:  Aggregates; TRIM44; autophagy; deubiquitinase; misfolded proteins; protein homeostasis; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1080/15548627.2021.1956105
  17. Mol Cell. 2021 Aug 02. pii: S1097-2765(21)00591-8. [Epub ahead of print]
    Spatiotemporal coordination of transcription preinitiation complex assembly in live cells.
    Vu Q Nguyen, Anand Ranjan, Sheng Liu, Xiaona Tang, Yick Hin Ling, Jan Wisniewski, Gaku Mizuguchi, Kai Yu Li, Vivian Jou, Qinsi Zheng, Luke D Lavis, Timothée Lionnet, Carl Wu.
      Transcription initiation by RNA polymerase II (RNA Pol II) requires preinitiation complex (PIC) assembly at gene promoters. In the dynamic nucleus, where thousands of promoters are broadly distributed in chromatin, it is unclear how multiple individual components converge on any target to establish the PIC. Here we use live-cell, single-molecule tracking in S. cerevisiae to visualize constrained exploration of the nucleoplasm by PIC components and Mediator's key role in guiding this process. On chromatin, TFIID/TATA-binding protein (TBP), Mediator, and RNA Pol II instruct assembly of a short-lived PIC, which occurs infrequently but efficiently within a few seconds on average. Moreover, PIC exclusion by nucleosome encroachment underscores regulated promoter accessibility by chromatin remodeling. Thus, coordinated nuclear exploration and recruitment to accessible targets underlies dynamic PIC establishment in yeast. Our study provides a global spatiotemporal model for transcription initiation in live cells.
    Keywords:  Mediator; Transcription initiation; live-cell imaging; single-molecule tracking; subdiffusion
    DOI:  https://doi.org/10.1016/j.molcel.2021.07.022
  18. Nat Struct Mol Biol. 2021 Aug;28(8): 662-670
    The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.
    Mark R Woodford, Alexander J Baker-Williams, Rebecca A Sager, Sarah J Backe, Adam R Blanden, Fiza Hashmi, Priyanka Kancherla, Alessandro Gori, David R Loiselle, Matteo Castelli, Stefano A Serapian, Giorgio Colombo, Timothy A Haystead, Sandra M Jensen, William G Stetler-Stevenson, Stewart N Loh, Laura S Schmidt, W Marston Linehan, Alaji Bah, Dimitra Bourboulia, Gennady Bratslavsky, Mehdi Mollapour.
      Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.
    DOI:  https://doi.org/10.1038/s41594-021-00633-2
  19. Front Immunol. 2021 ;12 714742
    Targeting Aging: Lessons Learned From Immunometabolism and Cellular Senescence.
    Dominique E Martin, Blake L Torrance, Laura Haynes, Jenna M Bartley.
      It is well known that aging is associated with dysregulated metabolism. This is seen both in terms of systemic metabolism, as well as at the cellular level with clear mitochondrial dysfunction. More recently, the importance of cellular metabolism in immune cells, or immunometabolism, has been highlighted as a major modifier of immune cell function. Indeed, T cell activation, differentiation, and effector function partly depend on alterations in metabolic pathways with different cell types and functionality favoring either glycolysis or oxidative phosphorylation. While immune system dysfunction with aging is well described, what remains less elucidated is how the integral networks that control immune cell metabolism are specifically affected by age. In recent years, this significant gap has been identified and work has begun to investigate the various ways immunometabolism could be impacted by both chronological age and age-associated symptoms, such as the systemic accumulation of senescent cells. Here, in this mini-review, we will examine immunometabolism with a focus on T cells, aging, and interventions, such as mTOR modulators and senolytics. This review also covers a timely perspective on how immunometabolism may be an ideal target for immunomodulation with aging.
    Keywords:  T cell; aging; geroscience; immunometabolism; senescence
    DOI:  https://doi.org/10.3389/fimmu.2021.714742
  20. Int J Clin Oncol. 2021 Aug 08.
    A phase II study of FOLFIRINOX with primary prophylactic pegfilgrastim for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.
    Mitsuhito Sasaki, Hideki Ueno, Shuichi Mitsunaga, Akihiro Ohba, Hiroko Hosoi, Satoshi Kobayashi, Makoto Ueno, Tetsuji Terazawa, Masahiro Goto, Dai Inoue, Shin Namiki, Yasunari Sakamoto, Shunsuke Kondo, Chigusa Morizane, Masafumi Ikeda, Takuji Okusaka.
       BACKGROUND: Although FOLFIRINOX is currently one of the standard therapies for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to evaluate the safety and efficacy of primary prophylactic pegfilgrastim with FOLFIRINOX in Japanese MPC patients.
    METHODS: FOLFIRINOX (intravenous oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, levofolinate 200 mg/m2, 5-fluorouracil (5-FU) bolus 400 mg/m2 and 5-FU 46 h infusion 2400 mg/m2) and pegfilgrastim 3.6 mg on day 4 or 5, every 2 weeks was administered to previously untreated MPC patients. The primary endpoint was the incidence of FN during the first 3 cycles. The planned sample size was 35 patients, but the trial was predefined to discontinue enrollment for safety if 4 patients developed FN.
    RESULTS: At the enrollment of 22 patients, 4 patients developed FN in the first cycle, resulting in an incidence of FN of 18% {95% confidence interval [CI], 0.5-40.3%}, and enrollment was discontinued early. The incidence of grade 3 or higher neutropenia was 36.4%. Median relative dose intensities during the initial 3 cycles of oxaliplatin, irinotecan, bolus 5-FU, infusional 5-FU, and levofolinate maintained high (100%, 89.0%, 100%, 66.0%, and 100%, respectively). Response rate and median overall survival were 54.5% (95% CI 32.7-74.9) and 15.7 months (95% CI 7.9-18.8), respectively.
    CONCLUSIONS: This phase II study could not demonstrate any reduction in the incidence of FN, nevertheless some patients experience benefits for efficacy by maintaining dose intensity using prophylactic pegfilgrastim.
    TRIAL REGISTRATION: http://www.umin.ac.jp/ctr/index-j.htm , UMIN000017538. Date of registration: May/13/2015.
    Keywords:  FOLFIRINOX; Febrile neutropenia; Pancreatic cancer; Pegfilgrastim
    DOI:  https://doi.org/10.1007/s10147-021-02001-y
  21. Trends Cell Biol. 2021 Aug 06. pii: S0962-8924(21)00142-2. [Epub ahead of print]
    Putative homeostatic role of cancer driver mutations.
    Avanthika Venkatachalam, Eli Pikarsky, Yinon Ben-Neriah.
      Somatic mutations have traditionally been associated with cancer, yet more recently, it was realized that they also appear in nontransformed cells beginning in early life. Remarkably, some of these mutations, commonly viewed as cancer driver mutations, are widely spread among cells of noncancerous tissues, sometimes affecting the majority of the tissue cells. This spreading process intensifies upon aging or exposure to extrinsic insults, such as UV irradiation, inhaling smoke, and inflammatory cues. Whereas classic driver mutations in normal cells are mostly viewed as a first step in the carcinogenesis process, here, we speculate that in certain states, they can play beneficial homeostatic roles while confronting stress and aging tissue repair.
    Keywords:  Tp53 hotspot mutations; beneficial mutations; clonal expansion; clonal fitness; clonal hematopoiesis
    DOI:  https://doi.org/10.1016/j.tcb.2021.07.002
  22. Cancer Cell. 2021 Aug 09. pii: S1535-6108(21)00388-3. [Epub ahead of print]39(8): 1059-1061
    The promise and peril of KRAS G12C inhibitors.
    Amanda R Moore, Shiva Malek.
      RAS mutant tumors have been largely refractory to therapies until now. Recent findings published in the New England Journal of Medicine show that sotorasib provides clinical benefit for KRAS p.G12C-mutated non-small-cell lung cancer (NSCLC) and provide mechanistic insights into acquired resistance to KRASG12C-specific inhibition.
    DOI:  https://doi.org/10.1016/j.ccell.2021.07.011
  23. Mol Cell. 2021 Jul 30. pii: S1097-2765(21)00590-6. [Epub ahead of print]
    A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies.
    Zhiwei Liu, Yingluo Liu, Lili Qian, Shangwen Jiang, Xiameng Gai, Shu Ye, Yuehong Chen, Xiaomin Wang, Linhui Zhai, Jun Xu, Congying Pu, Jing Li, Fuchu He, Min Huang, Minjia Tan.
      KRAS mutant cancer, characterized by the activation of a plethora of phosphorylation signaling pathways, remains a major challenge for cancer therapy. Despite recent advancements, a comprehensive profile of the proteome and phosphoproteome is lacking. This study provides a proteomic and phosphoproteomic landscape of 43 KRAS mutant cancer cell lines across different tissue origins. By integrating transcriptomics, proteomics, and phosphoproteomics, we identify three subsets with distinct biological, clinical, and therapeutic characteristics. The integrative analysis of phosphoproteome and drug sensitivity information facilitates the identification of a set of drug combinations with therapeutic potentials. Among them, we demonstrate that the combination of DOT1L and SHP2 inhibitors is an effective treatment specific for subset 2 of KRAS mutant cancers, corresponding to a set of TCGA clinical tumors with the poorest prognosis. Together, this study provides a resource to better understand KRAS mutant cancer heterogeneity and identify new therapeutic possibilities.
    Keywords:  DOT1L; KRAS mutation; SHP2; cancer; drug sensitivity; heterogeneity; phosphoproteomics; proteomics; subtype; therapy
    DOI:  https://doi.org/10.1016/j.molcel.2021.07.021
  24. Nutrients. 2021 Jul 09. pii: 2346. [Epub ahead of print]13(7):
    The Potential of Calorie Restriction and Calorie Restriction Mimetics in Delaying Aging: Focus on Experimental Models.
    Emiliana Giacomello, Luana Toniolo.
      Aging is a biological process determined by multiple cellular mechanisms, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, that ultimately concur in the functional decline of the individual. The evidence that the old population is steadily increasing and will triplicate in the next 50 years, together with the fact the elderlies are more prone to develop pathologies such as cancer, diabetes, and degenerative disorders, stimulates an important effort in finding specific countermeasures. Calorie restriction (CR) has been demonstrated to modulate nutrient sensing mechanisms, inducing a better metabolic profile, enhanced stress resistance, reduced oxidative stress, and improved inflammatory response. Therefore, CR and CR-mimetics have been suggested as powerful means to slow aging and extend healthy life-span in experimental models and humans. Taking into consideration the difficulties and ethical issues in performing aging research and testing anti-aging interventions in humans, researchers initially need to work with experimental models. The present review reports the major experimental models utilized in the study of CR and CR-mimetics, highlighting their application in the laboratory routine, and their translation to human research.
    Keywords:  aging; calorie restriction; calorie restriction mimetic; experimental models; health-span; life-span; resveratrol
    DOI:  https://doi.org/10.3390/nu13072346
  25. Trends Biochem Sci. 2021 Aug 09. pii: S0968-0004(21)00159-6. [Epub ahead of print]
    The lysosome as a master regulator of iron metabolism.
    Francesca Rizzollo, Sanket More, Peter Vangheluwe, Patrizia Agostinis.
      Intracellular iron fulfills crucial cellular processes, including DNA synthesis and mitochondrial metabolism, but also mediates ferroptosis, a regulated form of cell death driven by lipid-based reactive oxygen species (ROS). Beyond their established role in degradation and recycling, lysosomes occupy a central position in iron homeostasis and integrate metabolic and cell death signals emanating from different subcellular sites. We discuss the central role of the lysosome in preserving iron homeostasis and provide an integrated outlook of the regulatory circuits coupling the lysosomal system to the control of iron trafficking, interorganellar crosstalk, and ferroptosis induction. We also discuss novel studies unraveling how deregulated lysosomal iron-handling functions contribute to cancer, neurodegeneration, and viral infection, and can be harnessed for therapeutic interventions.
    Keywords:  cancer; ferroptosis; iron homeostasis; iron trafficking; neurodegenerative diseases; viruses
    DOI:  https://doi.org/10.1016/j.tibs.2021.07.003
  26. Science. 2021 08 13. 373(6556): 760-767
    Molecular phenotyping reveals the identity of Barrett's esophagus and its malignant transition.
    Karol Nowicki-Osuch, Lizhe Zhuang, Sriganesh Jammula, Christopher W Bleaney, Krishnaa T Mahbubani, Ginny Devonshire, Annalise Katz-Summercorn, Nils Eling, Anna Wilbrey-Clark, Elo Madissoon, John Gamble, Massimiliano Di Pietro, Maria O'Donovan, Kerstin B Meyer, Kourosh Saeb-Parsy, Andrew D Sharrocks, Sarah A Teichmann, John C Marioni, Rebecca C Fitzgerald.
      The origin of human metaplastic states and their propensity for cancer is poorly understood. Barrett's esophagus is a common metaplastic condition that increases the risk for esophageal adenocarcinoma, and its cellular origin is enigmatic. To address this, we harvested tissues spanning the gastroesophageal junction from healthy and diseased donors, including isolation of esophageal submucosal glands. A combination of single-cell transcriptomic profiling, in silico lineage tracing from methylation, open chromatin and somatic mutation analyses, and functional studies in organoid models showed that Barrett's esophagus originates from gastric cardia through c-MYC and HNF4A-driven transcriptional programs. Furthermore, our data indicate that esophageal adenocarcinoma likely arises from undifferentiated Barrett's esophagus cell types even in the absence of a pathologically identifiable metaplastic precursor, illuminating early detection strategies.
    DOI:  https://doi.org/10.1126/science.abd1449
  27. World J Gastroenterol. 2021 Jul 28. 27(28): 4582-4602
    Modulation of cell physiology under hypoxia in pancreatic cancer.
    Matias Estaras, Antonio Gonzalez.
      In solid tumors, the development of vasculature is, to some extent, slower than the proliferation of the different types of cells that form the tissue, both cancer and stroma cells. As a consequence, the oxygen availability is compromised and the tissue evolves toward a condition of hypoxia. The presence of hypoxia is variable depending on where the cells are localized, being less extreme at the periphery of the tumor and more severe in areas located deep within the tumor mass. Surprisingly, the cells do not die. Intracellular pathways that are critical for cell fate such as endoplasmic reticulum stress, apoptosis, autophagy, and others are all involved in cellular responses to the low oxygen availability and are orchestrated by hypoxia-inducible factor. Oxidative stress and inflammation are critical conditions that develop under hypoxia. Together with changes in cellular bioenergetics, all contribute to cell survival. Moreover, cell-to-cell interaction is established within the tumor such that cancer cells and the microenvironment maintain a bidirectional communication. Additionally, the release of extracellular vesicles, or exosomes, represents short and long loops that can convey important information regarding invasion and metastasis. As a result, the tumor grows and its malignancy increases. Currently, one of the most lethal tumors is pancreatic cancer. This paper reviews the most recent advances in the knowledge of how cells grow in a pancreatic tumor by adapting to hypoxia. Unmasking the physiological processes that help the tumor increase its size and their regulation will be of major relevance for the treatment of this deadly tumor.
    Keywords:  Cancer; Cell survival; Hypoxia; Pancreas; Proliferation; Tumor
    DOI:  https://doi.org/10.3748/wjg.v27.i28.4582
  28. Nat Mater. 2021 Aug 12.
    Next-generation cancer organoids.
    Bauer L LeSavage, Riley A Suhar, Nicolas Broguiere, Matthias P Lutolf, Sarah C Heilshorn.
      Organotypic models of patient-specific tumours are revolutionizing our understanding of cancer heterogeneity and its implications for personalized medicine. These advancements are, in part, attributed to the ability of organoid models to stably preserve genetic, proteomic, morphological and pharmacotypic features of the parent tumour in vitro, while also offering unprecedented genomic and environmental manipulation. Despite recent innovations in organoid protocols, current techniques for cancer organoid culture are inherently uncontrolled and irreproducible, owing to several non-standardized facets including cancer tissue sources and subsequent processing, medium formulations, and animal-derived three-dimensional matrices. Given the potential for cancer organoids to accurately recapitulate the intra- and intertumoral biological heterogeneity associated with patient-specific cancers, eliminating the undesirable technical variability accompanying cancer organoid culture is necessary to establish reproducible platforms that accelerate translatable insights into patient care. Here we describe the current challenges and recent multidisciplinary advancements and opportunities for standardizing next-generation cancer organoid systems.
    DOI:  https://doi.org/10.1038/s41563-021-01057-5
  29. Autophagy. 2021 Aug 12. 1-2
    Delineating the lipidated Atg8 structure for unveiling its hidden activity in autophagy.
    Tatsuro Maruyama, Nobuo N Noda.
      Atg8 has attracted attention as a central factor in autophagosome biogenesis for a long time. However, the molecular activities of Atg8 on the phagophore membranes as the physiologically functional lipidated form remain enigmatic. In our recent study, we unveiled the hidden physicochemical activity of lipidated Atg8 toward the membrane. Structural analysis revealed that lipidated Atg8 adopts a preferred orientation on the membrane, contacting the membrane using aromatic residues and at the same time exposing cargo binding pockets to the solvent, enabling this small protein to perturb and transform membranes while recognizing autophagic cargos. The membrane perturbation activity was shown to be essential for efficient autophagosome biogenesis, yet questions on the mechanistic roles of Atg8 remain open.
    Keywords:  Atg8; GUV; NMR; autophagosome; autophagy; lipidation; membrane perturbation; vacuolar morphology
    DOI:  https://doi.org/10.1080/15548627.2021.1961075
  30. J Genet Genomics. 2021 Aug 06. pii: S1673-8527(21)00229-0. [Epub ahead of print]
    Phase Separation in RNA Biology.
    Yi Lin, Xiaofeng Fang.
      Formation of biomolecular condensates via liquid-liquid phase separation (LLPS) is an advantageous strategy for cells to organize subcellular compartments for diverse functions. The involvement of LLPS is more widespread and overrepresented in RNA-related biological processes. This is in part because that RNAs are intrinsically multivalent macromolecules and the presence of RNAs affects the formation, dissolution and biophysical properties of biomolecular condensates formed by LLPS. Emerging studies have illustrated how LLPS participates in RNA transcription, splicing, processing, quality control, translation and function. The interconnected regulation between LLPS and RNAs ensures tight control of RNA-related cellular functions.
    Keywords:  Condensates; Membrane-less organelle; Phase separation; RNA biology
    DOI:  https://doi.org/10.1016/j.jgg.2021.07.012
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