bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022–11–27
34 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.
  2. Macroautophagy in quiescent and senescent cells: a pathway to longevity?
  3. Metabolic symbiosis in pancreatic cancer.
  4. Autophagy promotes cell survival by maintaining NAD levels.
  5. Hypoxia as a Regulator of Tumor Stroma and Metastasis.
  6. Glucocorticoid receptor and RAS: an unexpected couple in cancer.
  7. Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair.
  8. Cell Dissemination in Pancreatic Cancer.
  9. Extracellular SQSTM1 exacerbates acute pancreatitis by activating autophagy-dependent ferroptosis.
  10. Cancer metastasis is related to normal tissue stemness.
  11. Autophagic lysosome reformation in health and disease.
  12. Evaluation of single-cell RNA-seq clustering algorithms on cancer tumor datasets.
  13. A genome-wide CRISPR screen implicates plasma membrane asymmetry in exogenous C6-ceramide toxicity.
  14. cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis.
  15. Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction.
  16. A KLK6 Activity-Based Probe Reveals a Role for KLK6 Activity in Pancreatic Cancer Cell Invasion.
  17. Usefulness of the G8 Geriatric Assessment Tool as a Prognostic Factor in Gemcitabine Plus Nab-paclitaxel Combination Therapy for Elderly Patients with Pancreatic Cancer.
  18. Atypical CXCL12 signaling enhances neutrophil migration by modulating nuclear deformability.
  19. Tissue factor-induced fibrinogenesis mediates cancer cell clustering and multiclonal peritoneal metastasis.
  20. The future of engineered immune cell therapies.
  21. Glimmers of hope for targeting oncogenic KRAS-G12D.
  22. The Role of IL-6 in Cancer Cell Invasiveness and Metastasis-Overview and Therapeutic Opportunities.
  23. Tumour catabolism independent of malnutrition and inflammation in upper GI cancer patients revealed by longitudinal metabolomics.
  24. Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.
  25. Quantitative 3D correlative light and electron microscopy of organelle association during autophagy.
  26. Agent-based methods facilitate integrative science in cancer.
  27. Sedentary behavior and the biological hallmarks of aging.
  28. The Oncopig as an Emerging Model to Investigate Copper Regulation in Cancer.
  29. High precision, high throughput generation of droplets containing single cells.
  30. Mitochondrial permeability transition pore-dependent necrosis.
  31. Quantitative fate mapping: A general framework for analyzing progenitor state dynamics via retrospective lineage barcoding.
  32. Intracellular cholesterol transport inhibition Impairs autophagy flux by decreasing autophagosome-lysosome fusion.
  33. The molecular organization of differentially curved caveolae indicates bendable structural units at the plasma membrane.
  34. Temporal Association of Total Serum Cholesterol and Pancreatic Cancer Incidence.
  1. Nat Cancer. 2022 Nov 21.
    Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.
    Christopher J Halbrook, Galloway Thurston, Seth Boyer, Cecily Anaraki, Jennifer A Jiménez, Amy McCarthy, Nina G Steele, Samuel A Kerk, Hanna S Hong, Lin Lin, Fiona V Law, Catherine Felton, Lorenzo Scipioni, Peter Sajjakulnukit, Anthony Andren, Alica K Beutel, Rima Singh, Barbara S Nelson, Fran Van Den Bergh, Abigail S Krall, Peter J Mullen, Li Zhang, Sandeep Batra, Jennifer P Morton, Ben Z Stanger, Heather R Christofk, Michelle A Digman, Daniel A Beard, Andrea Viale, Ji Zhang, Howard C Crawford, Marina Pasca di Magliano, Claus Jorgensen, Costas A Lyssiotis.
      The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.
    DOI:  https://doi.org/10.1038/s43018-022-00463-1
  2. Trends Cell Biol. 2022 Nov 19. pii: S0962-8924(22)00235-5. [Epub ahead of print]
    Macroautophagy in quiescent and senescent cells: a pathway to longevity?
    Andrew Murley, Andrew Dillin.
      Cellular quiescence - reversible exit from the cell cycle - is an important feature of many cell types important for organismal health. Aging and cellular dysfunction compromise the survival and reactivation of quiescent cells over time. Studies suggest that autophagic processes and lysosomal function are critical to maintaining the function of quiescent cells, especially adult stem cells, throughout life. Findings also point to both pro-senescence and anti-senescence functions for macroautophagy depending on context. In this review, we will discuss these findings, unanswered questions on the role of macroautophagy and lysosomal function in quiescent and senescent cells, and the possibility for interventions that stimulate macroautophagy and lysosomes to promote quiescent cell function and tissue regeneration.
    Keywords:  aging; autophagy; lysosomes; quiescence; senescence
    DOI:  https://doi.org/10.1016/j.tcb.2022.10.004
  3. Nat Cancer. 2022 Nov 21.
    Metabolic symbiosis in pancreatic cancer.
    Dylan Gerard Ryan, Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s43018-022-00454-2
  4. Dev Cell. 2022 Nov 21. pii: S1534-5807(22)00760-2. [Epub ahead of print]57(22): 2584-2598.e11
    Autophagy promotes cell survival by maintaining NAD levels.
    Tetsushi Kataura, Lucia Sedlackova, Elsje G Otten, Ruchika Kumari, David Shapira, Filippo Scialo, Rhoda Stefanatos, Kei-Ichi Ishikawa, George Kelly, Elena Seranova, Congxin Sun, Dorothea Maetzel, Niall Kenneth, Sergey Trushin, Tong Zhang, Eugenia Trushina, Charles C Bascom, Ryan Tasseff, Robert J Isfort, John E Oblong, Satomi Miwa, Michael Lazarou, Rudolf Jaenisch, Masaya Imoto, Shinji Saiki, Manolis Papamichos-Chronakis, Ravi Manjithaya, Oliver D K Maddocks, Alberto Sanz, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components. Loss of autophagy in age-related human pathologies contributes to tissue degeneration through a poorly understood mechanism. Here, we identify an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD) levels, which are critical for cell survival. In respiring mouse fibroblasts with autophagy deficiency, loss of mitochondrial quality control was found to trigger hyperactivation of stress responses mediated by NADases of PARP and Sirtuin families. Uncontrolled depletion of the NAD(H) pool by these enzymes ultimately contributed to mitochondrial membrane depolarization and cell death. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient yeast, mouse fibroblasts, and human neurons. Our study provides a mechanistic link between autophagy and NAD metabolism and identifies targets for interventions in human diseases associated with autophagic, lysosomal, and mitochondrial dysfunction.
    Keywords:  DNA damage; NAD; PARP; Sirtuins; ageing; autophagy; metabolism; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.devcel.2022.10.008
  5. Am J Physiol Cell Physiol. 2022 Nov 21.
    Hypoxia as a Regulator of Tumor Stroma and Metastasis.
    Kyoung Eun Lee.
      Metastasis is the leading cause of mortality in most cancer patients. Despite its clinical importance, mechanistic underpinnings of metastatic progression remain poorly understood. Hypoxia, a condition of insufficient oxygen availability, frequently occurs in solid tumors because of their high oxygen/nutrient demand and abnormal tumor vasculature. In this review, we describe the roles of hypoxia and hypoxia-inducible factor (HIF) signaling in the metastatic cascade, with an emphasis on recent biological insights from in vivo studies.
    Keywords:  hypoxia; hypoxia-induced factor; metastasis; stroma; tumor microenvironment
    DOI:  https://doi.org/10.1152/ajpcell.00158.2022
  6. Trends Cell Biol. 2022 Nov 22. pii: S0962-8924(22)00253-7. [Epub ahead of print]
    Glucocorticoid receptor and RAS: an unexpected couple in cancer.
    Ion C Cirstea, Herwig P Moll, Jan Tuckermann.
      Constitutively activated rat sarcoma (RAS) GTPases are one of the major drivers of tumor growth and are difficult drug targets. The glucocorticoid receptor (GR), a nuclear receptor primarily acting in the nucleus, is a potent modulator of inflammation and regulator of metabolism and cell growth. Emerging evidence has revealed that GR modulates RAS-dependent signaling and RAS activation. The unliganded GR decreases RAS activation, and, upon ligand binding, GR leaves RAS complexes, is translocated into the nucleus, and unleashes the activation of RAS and its downstream pathways. GR forms a complex with RAS and RAF1 and their associated proteins, such as members of the 14-3-3 family of adapter proteins. The exploration of RAS-GR complex formation and maintenance will help to develop much-needed breakthroughs in oncogenic RAS biology and thus help to alleviate tumor growth and burden.
    Keywords:  Ras GTPases; cytoplasmic action; glucocorticoid receptor; tumor growth
    DOI:  https://doi.org/10.1016/j.tcb.2022.11.002
  7. EMBO J. 2022 Nov 21. e112677
    Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair.
    Maja Radulovic, Eva Maria Wenzel, Sania Gilani, Lya Kk Holland, Alf Håkon Lystad, Santosh Phuyal, Vesa M Olkkonen, Andreas Brech, Marja Jäättelä, Kenji Maeda, Camilla Raiborg, Harald Stenmark.
      Lysosome integrity is essential for cell viability, and lesions in lysosome membranes are repaired by the ESCRT machinery. Here, we describe an additional mechanism for lysosome repair that is activated independently of ESCRT recruitment. Lipidomic analyses showed increases in lysosomal phosphatidylserine and cholesterol after damage. Electron microscopy demonstrated that lysosomal membrane damage is rapidly followed by the formation of contacts with the endoplasmic reticulum (ER), which depends on the ER proteins VAPA/B. The cholesterol-binding protein ORP1L was recruited to damaged lysosomes, accompanied by cholesterol accumulation by a mechanism that required VAP-ORP1L interactions. The PtdIns 4-kinase PI4K2A rapidly produced PtdIns4P on lysosomes upon damage, and knockout of PI4K2A inhibited damage-induced accumulation of ORP1L and cholesterol and led to the failure of lysosomal membrane repair. The cholesterol-PtdIns4P transporter OSBP was also recruited upon damage, and its depletion caused lysosomal accumulation of PtdIns4P and resulted in cell death. We conclude that ER contacts are activated on damaged lysosomes in parallel to ESCRTs to provide lipids for membrane repair, and that PtdIns4P generation and removal are central in this response.
    Keywords:  cholesterol; lysosome; membrane contact site; membrane repair; phosphoinositide
    DOI:  https://doi.org/10.15252/embj.2022112677
  8. Cells. 2022 Nov 19. pii: 3683. [Epub ahead of print]11(22):
    Cell Dissemination in Pancreatic Cancer.
    Jungsun Kim.
      Pancreatic cancer is a disease notorious for its high frequency of recurrence and low survival rate. Surgery is the most effective treatment for localized pancreatic cancer, but most cancer recurs after surgery, and patients die within ten years of diagnosis. The question persists: what makes pancreatic cancer recur and metastasize with such a high frequency? Herein, we review evidence that subclinical dormant pancreatic cancer cells disseminate before developing metastatic or recurring cancer. We then discuss several routes by which pancreatic cancer migrates and the mechanisms by which pancreatic cancer cells adapt. Lastly, we discuss unanswered questions in pancreatic cancer cell migration and our perspectives.
    Keywords:  adherens junctions; cell dissemination; collective cell migration; epithelial–mesenchymal transition (EMT)
    DOI:  https://doi.org/10.3390/cells11223683
  9. Autophagy. 2022 Nov 25.
    Extracellular SQSTM1 exacerbates acute pancreatitis by activating autophagy-dependent ferroptosis.
    Liangchun Yang, Fanghua Ye, Jiao Liu, Daniel J Klionsky, Daolin Tang, Rui Kang.
      Acute pancreatitis (AP) is an abdominal inflammatory disease initiated by damaged pancreatic acinar cells and developed by systemic inflammation. SQSTM1 (sequestosome 1) has an intracellular function in mediating substrate degradation during macroautophagy/autophagy, and it can be released by macrophages and monocytes to trigger lethal inflammation during bacterial infection. Here, we report that extracellular SQSTM1 acts as a mediator of AP by enhancing the sensitivity to autophagy-dependent ferroptotic cell death. Serum SQSTM1 is elevated in AP patients as well as in mice that have cerulein-induced AP. The administration of SQSTM1-neutralizing antibodies protects against experimental AP in mice. Mechanistically, recombinant SQSTM1 protein (rSQSTM1) increases AGER (advanced glycosylation end-product specific receptor)-dependent ACSL4 (acyl-CoA synthetase long chain family member 4) expression, leading to polyunsaturated fatty acid production for autophagosome formation and subsequent ferroptosis. The rSQSTM1-elicited pathological responses during AP are attenuated in mice with the conditional deletion of Ager in the pancreas. These findings may provide not only new insights into the mechanism of autophagy-dependent cell death, but also suggest that targeting the extracellular SQSTM1 pathway is a potential strategy for the treatment of AP.
    Keywords:  SQSTM1; autophagy; ferroptosis; inflammation; lipid peroxidation; pancreatitis
    DOI:  https://doi.org/10.1080/15548627.2022.2152209
  10. PLoS One. 2022 ;17(11): e0277811
    Cancer metastasis is related to normal tissue stemness.
    Xing Yue Peng, Bocun Dong, Xiaohui Liu.
      The occurrence of cancer metastasis may be related to stem cells in normal tissues. We searched for patient IDs with both normal tissue stem cell values and TCGA (The Cancer Genome Atlas) clinical data for pairing and obtained 639 sets of data (stemness index of normal tissue, stemness index of tumor tissue, cancer stage, distant metastasis, tumor size) and invasion, and lymph node involvement). However, clinical data on cancer metastasis are of only four stages (e.g., Stage I, II, III, and IV), which cannot show subtle changes continuously. We need to find an effective data mining method to transform this four-valued clinical description into a numerical curve. We data-mine this data through numericalization, sorting, and noise reduction filtering. The results showed that: as the normal tissue stemness value (NS) increased, the tumor tissue stemness value (TS) increased proportionally (1.26 times NS). When NS >0.5, the rate of change in TS decelerated (0.43 times NS), and tumor metastasis began to occur. Clinical indicators, such as cancer stage, distant metastasis, tumor size and invasion, and lymph node involvement, showed that tumor metastasis became more and more severe with the increase of NS. This study suggests that tumor metastasis is triggered when the NS in the patient's body is more significant than 0.5.
    DOI:  https://doi.org/10.1371/journal.pone.0277811
  11. Autophagy. 2022 Nov 21. 1-18
    Autophagic lysosome reformation in health and disease.
    Randini Nanayakkara, Rajendra Gurung, Samuel J Rodgers, Matthew J Eramo, Georg Ramm, Christina A Mitchell, Meagan J McGrath.
      Lysosomes are the primary degradative compartment within cells and there have been significant advances over the past decade toward understanding how lysosome homeostasis is maintained. Lysosome repopulation ensures sustained autophagy function, a fundamental process that protects against disease. During macroautophagy/autophagy, cellular debris is sequestered into phagophores that mature into autophagosomes, which then fuse with lysosomes to generate autolysosomes in which contents are degraded. Autophagy cannot proceed without the sufficient generation of lysosomes, and this can be achieved via their de novo biogenesis. Alternatively, during autophagic lysosome reformation (ALR), lysosomes are generated via the recycling of autolysosome membranes. During this process, autolysosomes undergo significant membrane remodeling and scission to generate membrane fragments, that mature into functional lysosomes. By utilizing membranes already formed during autophagy, this facilitates an efficient pathway for re-deriving lysosomes, particularly under conditions of prolonged autophagic flux. ALR dysfunction is emerging as an important disease mechanism including for neurodegenerative disorders such as hereditary spastic paraplegia and Parkinson disease, neuropathies including Charcot-Marie-Tooth disease, lysosome storage disorders, muscular dystrophy, metabolic syndrome, and inflammatory and liver disorders. Here, we provide a comprehensive review of ALR, including an overview of its dynamic spatiotemporal regulation by MTOR and phosphoinositides, and the role ALR dysfunction plays in many diseases.
    Keywords:  Autophagic lysosome reformation; MTOR; PtdIns(4,5)P2; PtdIns4P; lysosome; phosphoinositide
    DOI:  https://doi.org/10.1080/15548627.2022.2128019
  12. Comput Struct Biotechnol J. 2022 ;20 6375-6387
    Evaluation of single-cell RNA-seq clustering algorithms on cancer tumor datasets.
    Alaina Mahalanabis, Andrei L Turinsky, Mia Husić, Erik Christensen, Ping Luo, Alaine Naidas, Michael Brudno, Trevor Pugh, Arun K Ramani, Parisa Shooshtari.
      Tumors are complex biological entities that comprise cell types of different origins, with different mutational profiles and different patterns of transcriptional dysregulation. The exploration of data related to cancer biology requires careful analytical methods to reflect the heterogeneity of cell populations in cancer samples. Single-cell techniques are now able to capture the transcriptional profiles of individual cells. However, the complexity of RNA-seq data, especially in cancer samples, makes it challenging to cluster single-cell profiles into groups that reflect the underlying cell types. We have developed a framework for a systematic examination of single-cell RNA-seq clustering algorithms for cancer data, which uses a range of well-established metrics to generate a unified quality score and algorithm ranking. To demonstrate this framework, we examined clustering performance of 15 different single-cell RNA-seq clustering algorithms on eight different cancer datasets. Our results suggest that the single-cell RNA-seq clustering algorithms fall into distinct groups by performance, with the highest clustering quality on non-malignant cells achieved by three algorithms: Seurat, bigSCale and Cell Ranger. However, for malignant cells, two additional algorithms often reach a better performance, namely Monocle and SC3. Their ability to detect known rare cell types was also among the best, along with Seurat. Our approach and results can be used by a broad audience of practitioners who analyze single-cell transcriptomic data in cancer research.
    Keywords:  Automated algorithms; Cancer; Clustering; Framework; Single-Cell RNA-seq
    DOI:  https://doi.org/10.1016/j.csbj.2022.10.029
  13. Biol Open. 2022 Nov 21. pii: bio.059695. [Epub ahead of print]
    A genome-wide CRISPR screen implicates plasma membrane asymmetry in exogenous C6-ceramide toxicity.
    Siti Nur Sarah Morris, Kirandeep K Deol, Mike Lange, James A Olzmann.
      The bioactive sphingolipid ceramide impacts diverse cellular processes (e.g., apoptosis and cell proliferation) through its effects on membrane dynamics and intracellular signalling pathways. The dysregulation of ceramide metabolism has been implicated in cancer evasion of apoptosis and targeting ceramide metabolism has potential therapeutic benefits as a strategy to kill cancer cells and slow tumor growth. However, the mechanisms of cancer cell resistance to ceramide-mediated cell death are vastly intertwined and incompletely understood. To shed light on this mystery, we performed a genome wide CRISPR-Cas9 screen to systematically identify regulators of cancer resistance to the soluble short chain ceramide, C6 ceramide (C6-Cer). Our results reveal a complex landscape of genetic modifiers of C6-Cer toxicity, including genes associated with ceramide and sphingolipid metabolism, vesicular trafficking, and membrane biology. Furthermore, we find that loss of the phospholipid flippase subunit TMEM30A impairs the plasma membrane trafficking of its binding partner, the P4-type ATPase ATP11B, and depletion of TMEM30A or ATP11B disrupts plasma membrane asymmetry and promotes resistance to C6-Cer toxicity. Together, our findings provide a resource of genetic modifiers of C6-Cer toxicity and reveal an unexpected role of plasma membrane asymmetry in C6-Cer induced cell death.
    Keywords:  CRISPR; Ceramide; Lipid; Lipotoxicity; Membrane; Screen; Sphingolipid
    DOI:  https://doi.org/10.1242/bio.059695
  14. Nat Cancer. 2022 Nov 22.
    cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis.
    Liqin Wang, Haojie Jin, Fleur Jochems, Siying Wang, Cor Lieftink, Isabel Mora Martinez, Giulia De Conti, Finn Edwards, Rodrigo Leite de Oliveira, Arnout Schepers, Yangyang Zhou, Jiaojiao Zheng, Wei Wu, Xingling Zheng, Shengxian Yuan, Jing Ling, Kathy Jastrzebski, Matheus Dos Santos Dias, Ji-Ying Song, Patrick N H Celie, Hideo Yagita, Ming Yao, Weiping Zhou, Roderick L Beijersbergen, Wenxin Qin, René Bernards.
      Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies; however, this remains challenging due to a lack of broadly acting senolytic drugs. Using CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify loss of the death receptor inhibitor cFLIP as a common vulnerability of senescent cancer cells. Senescent cells are primed for apoptotic death by NF-κB-mediated upregulation of death receptor 5 (DR5) and its ligand TRAIL, but are protected from death by increased cFLIP expression. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of a variety of senescent cancer cells. Moreover, senescent cells sensitize adjacent non-senescent cells to killing by DR5 agonist through a bystander effect mediated by secretion of cytokines. We validate this 'one-two punch' cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.
    DOI:  https://doi.org/10.1038/s43018-022-00462-2
  15. Elife. 2022 Nov 21. pii: e82860. [Epub ahead of print]11
    Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction.
    Jacob M Winter, Heidi L Fresenius, Corey N Cunningham, Peng Wei, Heather R Keys, Jordan A Berg, Alex J Bott, Tarun Yadav, Jeremy A Ryan, Deepika Sirohi, Sheryl R Tripp, Paige Barta, Neeraj Agarwal, Anthony Letai, David M Sabatini, Matthew L Wohlever, Jared Rutter.
      The tumor suppressor gene PTEN is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of PTEN itself, which frequently disrupts adjacent genes. Coincidental loss of PTEN-adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here we describe how the loss of ATAD1, which is adjacent to and frequently co-deleted with PTEN, predisposes cancer cells to apoptosis triggered by proteasome dysfunction and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic protein BIM from mitochondria to inactivate it. Cultured cells and mouse xenografts lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which activate BIM and trigger apoptosis. This work furthers our understanding of mitochondrial protein homeostasis and could lead to new therapeutic options for the hundreds of thousands of cancer patients who have tumors with chromosome 10q23 deletion.
    Keywords:  biochemistry; cancer biology; chemical biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.82860
  16. J Am Chem Soc. 2022 Nov 22.
    A KLK6 Activity-Based Probe Reveals a Role for KLK6 Activity in Pancreatic Cancer Cell Invasion.
    Leran Zhang, Scott Lovell, Elena De Vita, Pravin Kumar Ankush Jagtap, Daniel Lucy, Andrea Goya Grocin, Svend Kjær, Annabel Borg, Janosch Hennig, Aubry K Miller, Edward W Tate.
      Pancreatic cancer has the lowest survival rate of all common cancers due to late diagnosis and limited treatment options. Serine hydrolases are known to mediate cancer progression and metastasis through initiation of signaling cascades and cleavage of extracellular matrix proteins, and the kallikrein-related peptidase (KLK) family of secreted serine proteases have emerging roles in pancreatic ductal adenocarcinoma (PDAC). However, the lack of reliable activity-based probes (ABPs) to profile KLK activity has hindered progress in validation of these enzymes as potential targets or biomarkers. Here, we developed potent and selective ABPs for KLK6 by using a positional scanning combinatorial substrate library and characterized their binding mode and interactions by X-ray crystallography. The optimized KLK6 probe IMP-2352 (kobs/I = 11,000 M-1 s-1) enabled selective detection of KLK6 activity in a variety of PDAC cell lines, and we observed that KLK6 inhibition reduced the invasiveness of PDAC cells that secrete active KLK6. KLK6 inhibitors were combined with N-terminomics to identify potential secreted protein substrates of KLK6 in PDAC cells, providing insights into KLK6-mediated invasion pathways. These novel KLK6 ABPs offer a toolset to validate KLK6 and associated signaling partners as targets or biomarkers across a range of diseases.
    DOI:  https://doi.org/10.1021/jacs.2c07378
  17. JMA J. 2022 Oct 17. 5(4): 512-519
    Usefulness of the G8 Geriatric Assessment Tool as a Prognostic Factor in Gemcitabine Plus Nab-paclitaxel Combination Therapy for Elderly Patients with Pancreatic Cancer.
    Makoto Kadokura, Yuki Mori, Yumi Takenaka, Hiroki Yoda, Tomoki Yasumura, Keisuke Tanaka, Fumitake Amemiya.
       Introduction: The usefulness of various prognostic factors for advanced pancreatic cancer (APC) has been reported, but the number of elderly patients in these studies is disproportionately fewer than those in general practice. This study aimed to examine the prognostic factors for elderly patients with APC receiving gemcitabine plus nab-paclitaxel (GnP) considering the G8 geriatric assessment tool.
    Methods: We retrospectively analyzed 77 elderly (≥65 years old) patients with APC who received GnP as first-line chemotherapy at our hospital. We used the receiver operating characteristic curve to set the optimal cutoff value for G8. Univariate and multivariate Cox regression models were applied to study independent prognostic factors.
    Results: The progression-free survival was 5.5 months, and the overall survival (OS) was 12.0 months in all patients. The most optimal cutoff of G8 was 10.5. OS of G8 ≥10.5 patients was superior to that of G8 <10.5 patients (18.5 versus 8.0 months). Multivariate analysis showed that Eastern Cooperative Oncology Group performance status 1 (hazard ratio [HR] 3.00, p = 0.02), neutrophil-lymphocyte ratio ≥3.9 (HR 2.73, p = 0.03), and G8 geriatric assessment <10.5 (HR 5.38, p < 0.001) were independent negative prognostic factors.
    Conclusions: G8 is useful for predicting prognoses in elderly patients with APC receiving GnP.
    Keywords:  G8 geriatric assessment tool; Pancreatic cancer; gemcitabine plus nab-paclitaxel; neutrophil-lymphocyte ratio; prognostic factor
    DOI:  https://doi.org/10.31662/jmaj.2022-0086
  18. Sci Signal. 2022 Nov 22. 15(761): eabk2552
    Atypical CXCL12 signaling enhances neutrophil migration by modulating nuclear deformability.
    Bianca Calì, Mathieu Deygas, Fabio Munari, Elisabetta Marcuzzi, Antonino Cassará, Lara Toffali, Massimo Vetralla, Mathilde Bernard, Matthieu Piel, Onelia Gagliano, Marta Mastrogiovanni, Carlo Laudanna, Nicola Elvassore, Barbara Molon, Pablo Vargas, Antonella Viola.
      To reach inflamed tissues from the circulation, neutrophils must overcome physical constraints imposed by the tissue architecture, such as the endothelial barrier or the three-dimensional (3D) interstitial space. In these microenvironments, neutrophils are forced to migrate through spaces smaller than their own diameter. One of the main challenges for cell passage through narrow gaps is the deformation of the nucleus, the largest and stiffest organelle in cells. Here, we showed that chemokines, the extracellular signals that guide cell migration in vivo, modulated nuclear plasticity to support neutrophil migration in restricted microenvironments. Exploiting microfabricated devices, we found that the CXC chemokine CXCL12 enhanced the nuclear pliability of mouse bone marrow-derived neutrophils to sustain their migration in 3D landscapes. This previously uncharacterized function of CXCL12 was mediated by the atypical chemokine receptor ACKR3 (also known as CXCR7), required protein kinase A (PKA) activity, and induced chromatin compaction, which resulted in enhanced cell migration in 3D. Thus, we propose that chemical cues regulate the nuclear plasticity of migrating leukocytes to optimize their motility in restricted microenvironments.
    DOI:  https://doi.org/10.1126/scisignal.abk2552
  19. Cancer Lett. 2022 Oct 28. pii: S0304-3835(22)00470-0. [Epub ahead of print]553 215983
    Tissue factor-induced fibrinogenesis mediates cancer cell clustering and multiclonal peritoneal metastasis.
    Makoto Miyazaki, Ayaka Nakabo, Yoshiko Nagano, Yuko Nagamura, Kazuyoshi Yanagihara, Rieko Ohki, Yoshikazu Nakamura, Kiyoko Fukami, Jun Kawamoto, Kenji Umayahara, Masaru Sakamoto, Keiichi Iwaya, Hideki Yamaguchi.
      Peritoneal metastasis is one of the most frequent causes of death in several types of advanced cancers; however, the underlying molecular mechanisms remain largely unknown. In this study, we exploited multicolor fluorescent lineage tracking to investigate the clonality of peritoneal metastasis in mouse xenograft models. When peritoneal metastasis was induced by intraperitoneal or orthotopic injection of multicolored cancer cells, each peritoneally metastasized tumor displayed multicolor fluorescence regardless of metastasis sites, indicating that it consists of multiclonal cancer cell populations. Multicolored cancer cell clusters form within the peritoneal cavity and collectively attach to the peritoneum. In vitro, peritoneal lavage fluid or cleared ascitic fluid derived from cancer patients induces cancer cell clustering, which is inhibited by anticoagulants. Cancer cell clusters formed in vitro and in vivo are associated with fibrin formation. Furthermore, tissue factor knockout in cancer cells abrogates cell clustering, peritoneal attachment, and peritoneal metastasis. Thus, we propose that cancer cells activate the coagulation cascade via tissue factor to form fibrin-mediated cell clusters and promote peritoneal attachment; these factors lead to the development of multiclonal peritoneal metastasis and may be therapeutic targets.
    Keywords:  Fibrinogenesis; Fluorescent lineage tracking; Multiclonal metastasis; Peritoneal metastasis; Tissue factor
    DOI:  https://doi.org/10.1016/j.canlet.2022.215983
  20. Science. 2022 Nov 25. 378(6622): 853-858
    The future of engineered immune cell therapies.
    Darrell J Irvine, Marcela V Maus, David J Mooney, Wilson W Wong.
      Immune cells are being engineered to recognize and respond to disease states, acting as a "living drug" when transferred into patients. Therapies based on engineered immune cells are now a clinical reality, with multiple engineered T cell therapies approved for treatment of hematologic malignancies. Ongoing preclinical and clinical studies are testing diverse strategies to modify the fate and function of immune cells for applications in cancer, infectious disease, and beyond. Here, we discuss current progress in treating human disease with immune cell therapeutics, emerging strategies for immune cell engineering, and challenges facing the field, with a particular emphasis on the treatment of cancer, where the most effort has been applied to date.
    DOI:  https://doi.org/10.1126/science.abq6990
  21. Cancer Gene Ther. 2022 Nov 21.
    Glimmers of hope for targeting oncogenic KRAS-G12D.
    Daolin Tang, Rui Kang.
      KRAS mutations are one of the most common genetic abnormalities in cancer, especially lung, colon, and pancreatic cancers. Strategies targeting the oncogenic KRAS pathway include direct and indirect approaches. KRAS-G12C inhibitors developed based on binding to the switch II pocket structure of KRAS mutant protein represent a breakthrough in the development of targeted therapeutic strategies against oncogenic proteins previously considered undruggable. The covalent KRAS-G12C inhibitors sotorasib (AMG510) and adagrasib (MRTX849) are used to treat patients with KRAS-G12C-mutated non-small cell lung cancer. Emerging research shows that other host point mutations in KRAS can also be directly targeted by small-molecule compounds. Recently, through extensive structure-based drug design from Mirati Therapeutics, a novel non-covalent KRAS-G12D inhibitor, MRTX1133, showed significant preclinical antitumor activity in KRAS-G12D-bearing tumor cells, especially pancreatic ductal adenocarcinoma. Here, we discuss the selectivity, efficacy, toxicity, and potential application challenges of this novel targeted protein inhibitor.
    DOI:  https://doi.org/10.1038/s41417-022-00561-3
  22. Cells. 2022 Nov 21. pii: 3698. [Epub ahead of print]11(22):
    The Role of IL-6 in Cancer Cell Invasiveness and Metastasis-Overview and Therapeutic Opportunities.
    Magdalena Rašková, Lukáš Lacina, Zdeněk Kejík, Anna Venhauerová, Markéta Skaličková, Michal Kolář, Milan Jakubek, Daniel Rosel, Karel Smetana, Jan Brábek.
      Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role of IL-6 signalling pathways in cancer biology, with particular emphasis on cancer cell invasiveness and metastasis formation. Targeting principal components of IL-6 signalling (e.g., IL-6Rs, gp130, STAT3, NF-κB) is an intensively studied approach in preclinical cancer research. It is of significant translational potential; numerous studies strongly imply the remarkable potential of IL-6 signalling inhibitors, especially in metastasis suppression.
    Keywords:  IL-6; cancer; metastasis
    DOI:  https://doi.org/10.3390/cells11223698
  23. J Cachexia Sarcopenia Muscle. 2022 Nov 23.
    Tumour catabolism independent of malnutrition and inflammation in upper GI cancer patients revealed by longitudinal metabolomics.
    Janusz von Renesse, Felix von Bechtolsheim, Sophie Jonas, Lena Seifert, Tiago C Alves, Adrian M Seifert, Filip Komorek, Guergana Tritchkova, Mario Menschikowski, Ulrich Bork, Ronny Meisterfeld, Marius Distler, Triantafyllos Chavakis, Jürgen Weitz, Alexander M Funk, Christoph Kahlert, Peter Mirtschink.
       BACKGROUND: The detrimental impact of malnutrition and cachexia in cancer patients subjected to surgical resection is well established. However, how systemic and local metabolic alterations in cancer patients impact the serum metabolite signature, thereby leading to cancer-specific differences, is poorly defined. In order to implement metabolomics as a potential tool in clinical diagnostics and disease follow-up, targeted metabolite profiling based on quantitative measurements is essential. We hypothesized that the quantitative metabolic profile assessed by 1 H nuclear magnetic resonance (NMR) spectroscopy can be used to identify cancer-induced catabolism and potentially distinguish between specific tumour entities. Importantly, to prove tumour dependency and assess metabolic normalization, we additionally analysed the metabolome of patients' sera longitudinally post-surgery in order to assess metabolic normalization.
    METHODS: Forty two metabolites in sera of patients with tumour entities known to cause malnutrition and cachexia, namely, upper gastrointestinal cancer and pancreatic cancer, as well as sera of healthy controls, were quantified by 1 H NMR spectroscopy.
    RESULTS: Comparing serum metabolites of patients with gastrointestinal cancer with healthy controls and pancreatic cancer patients, we identified at least 15 significantly changed metabolites in each comparison. Principal component and pathway analysis tools showed a catabolic signature in preoperative upper gastrointestinal cancer patients. The most specifically upregulated metabolite group in gastrointestinal cancer patients was ketone bodies (3-hydroxybutyrate, P < 0.0001; acetoacetate, P < 0.0001; acetone, P < 0.0001; false discovery rate [FDR] adjusted). Increased glycerol levels (P < 0.0001), increased concentration of the ketogenic amino acid lysine (P = 0.03) and a significant correlation of 3-hydroxybutyrate levels with branched-chained amino acids (leucine, P = 0.02; isoleucine, P = 0.04 [FDR adjusted]) suggested that ketone body synthesis was driven by lipolysis and amino acid breakdown. Interestingly, the catabolic signature was independent of the body mass index, clinically assessed malnutrition using the nutritional risk screening score, and systemic inflammation assessed by CRP and leukocyte count. Longitudinal measurements and principal component analyses revealed a quick normalization of key metabolic alterations seven days post-surgery, including ketosis.
    CONCLUSIONS: Together, the quantitative metabolic profile obtained by 1 H NMR spectroscopy identified a tumour-induced catabolic signature specific to upper gastrointestinal cancer patients and enabled monitoring restoration of metabolic homeostasis after surgery. This approach was critical to identify the obtained metabolic profile as an upper gastrointestinal cancer-specific signature independent of malnutrition and inflammation.
    Keywords:  3-Hydroxybutyrate; Gastrointestinal cancer; Ketone bodies; Metabolic profile; Metabolome; NMR
    DOI:  https://doi.org/10.1002/jcsm.13131
  24. Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01564-9. [Epub ahead of print]41(8): 111690
    Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.
    Yahyah Aman, Annmary Paul Erinjeri, Nikolaos Tataridas-Pallas, Rhianna Williams, Rachel Wellman, Hannah Chapman, John Labbadia.
      The age-related loss of protein homeostasis (proteostasis) is at the heart of numerous neurodegenerative diseases. Therefore, finding ways to preserve proteome integrity in aged cells may be a powerful way to promote long-term health. Here, we show that reducing the activity of a highly conserved mitochondrial outer membrane protein, MTCH-1/MTCH2, suppresses age-related proteostasis collapse in Caenorhabditis elegans without disrupting development, growth, or reproduction. Loss of MTCH-1 does not influence proteostasis capacity in aged tissues through previously described pathways but instead operates by reducing CED-4 levels. This results in the sequestration of HSP-90 by inactive CED-3, which in turn leads to an increase in HSF-1 activity, transcriptional remodeling of the proteostasis network, and maintenance of proteostasis capacity with age. Together, our findings reveal a role for programmed cell death factors in determining proteome health and suggest that inhibiting MTCH-1 activity in adulthood may safeguard the aging proteome and suppress age-related diseases.
    Keywords:  CP: Cell biology; Caenorhabditis elegans; HSF-1; HSP90; MTCH-1; aging; mitochondria; molecular chaperones; programmed cell death; protein homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111690
  25. Cell Struct Funct. 2022 Nov 22.
    Quantitative 3D correlative light and electron microscopy of organelle association during autophagy.
    Satoru Takahashi, Chieko Saito, Ikuko Koyama-Honda, Noboru Mizushima.
      In macroautophagy, disk-shaped double-membrane structures called phagophores elongate to form cup-shaped structures, becoming autophagosomes upon closure. These autophagosomes then fuse with lysosomes to become autolysosomes and degrade engulfed material. Autophagosome formation is reported to involve other organelles, including the endoplasmic reticulum (ER) and mitochondria. Organelles are also taken up by autophagosomes as autophagy cargos. However, few studies have performed systematic spatiotemporal analysis of inter-organelle relationships during macroautophagy. Here, we investigated the organelles in contact with phagophores, autophagosomes, and autolysosomes by using three-dimensional correlative light and electron microscopy with array tomography in cells starved 30 min. As previously reported, all phagophores associate with the ER. The surface area of phagophores in contact with the ER decreases gradually as they mature into autophagosomes and autolysosomes. However, the ER still associates with 92% of autophagosomes and 79% of autolysosomes, suggesting that most autophagosomes remain on the ER after closure and even when they fuse with lysosomes. In addition, we found that phagophores form frequently near other autophagic structures, suggesting the presence of potential hot spots for autophagosome formation. We also analyzed the contents of phagophores and autophagosomes and found that the ER is the most frequently engulfed organelle (detected in 65% of total phagophores and autophagosomes). These quantitative three-dimensional ultrastructural data provide insights into autophagosome-organelle relationships during macroautophagy. Key words: 3D-CLEM, autophagosome, electron microscopy, endoplasmic reticulum, lysosome.
    Keywords:  3D-CLEM; autophagosome; electron microscopy; endoplasmic reticulum; lysosome
    DOI:  https://doi.org/10.1247/csf.22071
  26. Trends Cell Biol. 2022 Nov 17. pii: S0962-8924(22)00240-9. [Epub ahead of print]
    Agent-based methods facilitate integrative science in cancer.
    Jeffrey West, Mark Robertson-Tessi, Alexander R A Anderson.
      In this opinion, we highlight agent-based modeling as a key tool for exploration of cell-cell and cell-environment interactions that drive cancer progression, therapeutic resistance, and metastasis. These biological phenomena are particularly suited to be captured at the cell-scale resolution possible only within agent-based or individual-based mathematical models. These modeling approaches complement experimental work (in vitro and in vivo systems) through parameterization and data extrapolation but also feed forward to drive new experiments that test model-generated predictions.
    Keywords:  agent-based mathematical models; cancer metabolism; immune–tumor interactions; integrative science; tissue homeostasis
    DOI:  https://doi.org/10.1016/j.tcb.2022.10.006
  27. Ageing Res Rev. 2022 Nov 21. pii: S1568-1637(22)00249-5. [Epub ahead of print] 101807
    Sedentary behavior and the biological hallmarks of aging.
    Jérémy Raffin, Philipe de Souto Barreto, Anne Pavy Le Traon, Bruno Vellas, Mylène Aubertin-Leheudre, Yves Rolland.
      While the benefits of physical exercise for a healthy aging are well-recognized, a growing body of evidence shows that sedentary behavior has deleterious health effects independently, to some extent, of physical activity levels. Yet, the increasing prevalence of sedentariness constitutes a major public health issue that contributes to premature aging but the potential cellular mechanisms through which prolonged immobilization may accelerate biological aging remain unestablished. This narrative review summarizes the impact of sedentary behavior using different models of extreme sedentary behaviors including bedrest, unilateral limb suspension and space travel studies, on the hallmarks of aging 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. We further highlight the remaining knowledge gaps that need more research in order to promote healthspan extension and to provide future contributions to the field of geroscience.
    Keywords:  Hallmarks of aging; bedrest; lower limb suspension; sedentary behavior; spaceflight
    DOI:  https://doi.org/10.1016/j.arr.2022.101807
  28. Int J Mol Sci. 2022 Nov 13. pii: 14012. [Epub ahead of print]23(22):
    The Oncopig as an Emerging Model to Investigate Copper Regulation in Cancer.
    Alyssa L Carlson, Jaime Carrazco-Carrillo, Aaron Loder, Lobna Elkhadragy, Kyle M Schachtschneider, Teresita Padilla-Benavides.
      Emerging evidence points to several fundamental contributions that copper (Cu) has to promote the development of human pathologies such as cancer. These recent and increasing identification of the roles of Cu in cancer biology highlights a promising field in the development of novel strategies against cancer. Cu and its network of regulatory proteins are involved in many different contextual aspects of cancer from driving cell signaling, modulating cell cycle progression, establishing the epithelial-mesenchymal transition, and promoting tumor growth and metastasis. Human cancer research in general requires refined models to bridge the gap between basic science research and meaningful clinical trials. Classic studies in cultured cancer cell lines and animal models such as mice and rats often present caveats when extended to humans due to inherent genetic and physiological differences. However, larger animal models such as pigs are emerging as more appropriate tools for translational research as they present more similarities with humans in terms of genetics, anatomical structures, organ sizes, and pathological manifestations of diseases like cancer. These similarities make porcine models well-suited for addressing long standing questions in cancer biology as well as in the arena of novel drug and therapeutic development against human cancers. With the emergent roles of Cu in human health and pathology, the pig presents an emerging and valuable model to further investigate the contributions of this metal to human cancers. The Oncopig Cancer Model is a transgenic swine model that recapitulates human cancer through development of site and cell specific tumors. In this review, we briefly outline the relationship between Cu and cancer, and how the novel Oncopig Cancer Model may be used to provide a better understanding of the mechanisms and causal relationships between Cu and molecular targets involved in cancer.
    Keywords:  Oncopig; copper; cuproproteins; homeostasis; metal transport
    DOI:  https://doi.org/10.3390/ijms232214012
  29. Lab Chip. 2022 Nov 23.
    High precision, high throughput generation of droplets containing single cells.
    Jiande Zhou, Amaury Wei, Arnaud Bertsch, Philippe Renaud.
      The Poisson limit is a major problem for the isolation of single cells in different single-cell technologies and applications. In droplet-based single-cell assays, a scheme that is increasingly popular, the intrinsic randomness during single-cell encapsulation in droplets requires most of the created droplets to be empty, which has a profound impact on the efficiency and throughput of such techniques, and on the predictability of the combinatory droplet assays. Here we present a simple passive microfluidic system overcoming this limitation with unprecedented efficacy, allowing the generation of single-cell droplets for a wide range of operating conditions, with extremely high throughput (more than 22 000 single-cell loaded droplets per minute) and with an extremely low fault ratio (doublets or empty droplets), applicable to any cells and deformable particles. This versatile technique will shift the paradigm of single-cell encapsulation and will impact single-cell sequencing, rare cell isolation, multicellular/bead studies in immunology or cancer biology, etc.
    DOI:  https://doi.org/10.1039/d2lc00841f
  30. J Mol Cell Cardiol. 2022 Nov 18. pii: S0022-2828(22)00563-6. [Epub ahead of print]
    Mitochondrial permeability transition pore-dependent necrosis.
    Dexter J Robichaux, Mikako Harata, Elizabeth Murphy, Jason Karch.
      Mitochondrial permeability transition pore (mPTP)-dependent necrotic cell death is a form of necrotic cell death that is driven by mitochondrial dysfunction by the opening of the mPTP and is triggered by increases in matrix levels of Ca2+ and reactive oxygen species. This form of cell death has been implicated in ischemic injuries of the heart and brain as well as numerous degenerative diseases in the brain and skeletal muscle. This review focuses on the molecular triggers and regulators of mPTP-dependent necrosis in the context of myocardial ischemia reperfusion injury. Research over the past 50 years has led to the identity of regulators and putative pore-forming components of the mPTP. Finally, downstream consequences of activation of the mPTP as well as ongoing questions and areas of research are discussed. These questions pose a particular interest as targeting the mPTP could potentially represent an efficacious therapeutic strategy to reduce infarct size following an ischemic event.
    Keywords:  ANT; ATP synthase; BAK; BAX; Calcium; CypD; Ischemia reperfusion; MPTP; Mitochondria; Mitochondrial dysfunction; Necrosis; Permeability transition; ROS
    DOI:  https://doi.org/10.1016/j.yjmcc.2022.11.003
  31. Cell. 2022 Nov 23. pii: S0092-8674(22)01374-5. [Epub ahead of print]185(24): 4604-4620.e32
    Quantitative fate mapping: A general framework for analyzing progenitor state dynamics via retrospective lineage barcoding.
    Weixiang Fang, Claire M Bell, Abel Sapirstein, Soichiro Asami, Kathleen Leeper, Donald J Zack, Hongkai Ji, Reza Kalhor.
      Natural and induced somatic mutations that accumulate in the genome during development record the phylogenetic relationships of cells; whether these lineage barcodes capture the complex dynamics of progenitor states remains unclear. We introduce quantitative fate mapping, an approach to reconstruct the hierarchy, commitment times, population sizes, and commitment biases of intermediate progenitor states during development based on a time-scaled phylogeny of their descendants. To reconstruct time-scaled phylogenies from lineage barcodes, we introduce Phylotime, a scalable maximum likelihood clustering approach based on a general barcoding mutagenesis model. We validate these approaches using realistic in silico and in vitro barcoding experiments. We further establish criteria for the number of cells that must be analyzed for robust quantitative fate mapping and a progenitor state coverage statistic to assess the robustness. This work demonstrates how lineage barcodes, natural or synthetic, enable analyzing progenitor fate and dynamics long after embryonic development in any organism.
    Keywords:  ICE-FASE; Phylotime; clonal dynamics; coalescent theory; homing CRISPR MARC1 barcoding; phylogenetic inference; progenitor field dynamics; single cell ineage tracing; somatic mutations; time-scaled cell phylogeny
    DOI:  https://doi.org/10.1016/j.cell.2022.10.028
  32. Cell Commun Signal. 2022 Nov 25. 20(1): 189
    Intracellular cholesterol transport inhibition Impairs autophagy flux by decreasing autophagosome-lysosome fusion.
    Yunash Maharjan, Raghbendra Kumar Dutta, Jinbae Son, Xiaofan Wei, Channy Park, Hyug Moo Kwon, Raekil Park.
       BACKGROUND: Autophagy is an intracellular degradation process crucial for homeostasis. During autophagy, a double-membrane autophagosome fuses with lysosome through SNARE machinery STX17 to form autolysosome for degradation of damaged organelle. Whereas defective autophagy enhances cholesterol accumulation in the lysosome and impaired autophagic flux that results Niemann-Pick type C1 (NPC1) disease. However, exact interconnection between NPC1 and autophagic flux remain obscure due to the existence of controversial reports.
    RESULTS: This study aimed at a comparison of the effects of three autophagic inhibitor drugs, including chloroquine, U18666A, and bafilomycin A1, on the intracellular cholesterol transport and autophagy flux. Chloroquine, an autophagic flux inhibitor; U1866A, a NPC1 inhibitor, and bafilomycin A, a lysosomotropic agent are well known to inhibit autophagy by different mechanism. Here we showed that treatment with U1866A and bafilomycin A induces lysosomal cholesterol accumulation that prevented autophagic flux by decreasing autophagosome-lysosome fusion. We also demonstrated that accumulation of cholesterol within the lysosome did not affect lysosomal pH. Although the clearance of accumulated cholesterol by cyclodextrin restored the defective autophagosome-lysosome fusion, the autophagy flux restoration was possible only when lysosomal acidification was not altered. In addition, a failure of STX17 trafficking to autophagosomes plays a key role in prevention of autophagy flux caused by intracellular cholesterol transport inhibitors.
    CONCLUSIONS: Our data provide a new insight that the impaired autophagy flux does not necessarily result in lysosomal cholesterol accumulation even though it prevents autophagosome-lysosome fusion. Video abstract.
    Keywords:  Autophagosomes; Autophagy flux; Bafilomycin A1; Chloroquine; Intracellular cholesterol transport; STX17; U18666A
    DOI:  https://doi.org/10.1186/s12964-022-00942-z
  33. Nat Commun. 2022 Nov 24. 13(1): 7234
    The molecular organization of differentially curved caveolae indicates bendable structural units at the plasma membrane.
    Claudia Matthaeus, Kem A Sochacki, Andrea M Dickey, Dmytro Puchkov, Volker Haucke, Martin Lehmann, Justin W Taraska.
      Caveolae are small coated plasma membrane invaginations with diverse functions. Caveolae undergo curvature changes. Yet, it is unclear which proteins regulate this process. To address this gap, we develop a correlative stimulated emission depletion (STED) fluorescence and platinum replica electron microscopy imaging (CLEM) method to image proteins at single caveolae. Caveolins and cavins are found at all caveolae, independent of curvature. EHD2 is detected at both low and highly curved caveolae. Pacsin2 associates with low curved caveolae and EHBP1 with mostly highly curved caveolae. Dynamin is absent from caveolae. Cells lacking dynamin show no substantial changes to caveolae, suggesting that dynamin is not directly involved in caveolae curvature. We propose a model where caveolins, cavins, and EHD2 assemble as a cohesive structural unit regulated by intermittent associations with pacsin2 and EHBP1. These coats can flatten and curve to enable lipid traffic, signaling, and changes to the surface area of the cell.
    DOI:  https://doi.org/10.1038/s41467-022-34958-3
  34. Nutrients. 2022 Nov 21. pii: 4938. [Epub ahead of print]14(22):
    Temporal Association of Total Serum Cholesterol and Pancreatic Cancer Incidence.
    Qiao-Li Wang, Jaewon Khil, SungEun Hong, Dong Hoon Lee, Kyoung Hwa Ha, NaNa Keum, Hyeon Chang Kim, Edward L Giovannucci.
      Previous studies have suggested a "cholesterol-lowering effect" of preclinical pancreatic cancer, suggesting lower total cholesterol as a potential diagnostic marker. Leveraging repeated measurements of total cholesterol, this study aims to examine the temporal association of total cholesterol and pancreatic cancer incidence. We conducted a nested case-control study based on a Korean National Health Insurance Service-Health Screening Cohort, including 215 pancreatic cancer cases and 645 controls matched on age and sex. Conditional logistic regression was applied to estimate the odds ratio (OR) and 95% confidence interval (CI) for the associations of pancreatic cancer incidence with total cholesterol levels across different time windows over 11 years before pancreatic cancer diagnosis (recent, mid, distant). We found that, compared to participants with total cholesterol &lt; 200 mg/dL in the recent 3 years prior to diagnosis, those having total cholesterol ≥ 240 mg/dL showed a significantly lower pancreatic cancer incidence (OR = 0.50 (0.27-0.93)). No significant association was found in relation to total cholesterol measured in the mid and distant past. When changes in total cholesterol over the three time periods were analyzed, compared with those with total cholesterol levels consistently below 240 mg/dL over the entire period, the OR of pancreatic cancer was 0.45 (0.20-1.03) for participants with recent-onset hypercholesterolemia, 1.89 (0.95-3.75) for recent-resolved hypercholesterolemia, and 0.71 (0.30-1.66) for consistent hypercholesterolemia. In conclusion, while high total cholesterol in the recent past may indicate a lower pancreatic cancer incidence, a recent decrease in total cholesterol may suggest an elevated incidence of pancreatic cancer.
    Keywords:  blood; incidence; lipid; pancreatic ductal adenocarcinoma; timing
    DOI:  https://doi.org/10.3390/nu14224938
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