bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023‒01‒29
35 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Isolation of extracellular fluids reveals novel secreted bioactive proteins from muscle and fat tissues.
  2. Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors.
  3. Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging.
  4. The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy.
  5. Investigating trajectories of aging using high-dimensional phenotyping in mice.
  6. A census of complexes formed by mitochondrial proteins.
  7. Characterization of proteome-size scaling by integrative omics reveals mechanisms of proliferation control in cancer.
  8. Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication.
  9. The molecular biology of peritoneal metastatic disease.
  10. Multitasking dynamic contrast enhanced magnetic resonance imaging can accurately differentiate chronic pancreatitis from pancreatic ductal adenocarcinoma.
  11. Comprehensive characterization of complex glycosphingolipids in human pancreatic cancer tissues.
  12. Mitochondrial complexome reveals quality-control pathways of protein import.
  13. Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination.
  14. Neutrophil-activating therapy for the treatment of cancer.
  15. Insights into the role of senescence in tumor dormancy: mechanisms and applications.
  16. Involvement of redox signalling in tumour cell dormancy and metastasis.
  17. The role of glycans in the mechanobiology of cancer.
  18. Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis.
  19. Reappraisal of Tumor Deposit as a Prognostic Factor in Pancreatic Cancer.
  20. Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules.
  21. MitoStores: chaperone-controlled protein granules store mitochondrial precursors in the cytosol.
  22. Exon architecture controls mRNA m6A suppression and gene expression.
  23. Pan-Cancer landscape of protein activities identifies drivers of signalling dysregulation and patient survival.
  24. The Latest Treatments for Cancer Cachexia: An Overview.
  25. Whole-mouse clearing and imaging at the cellular level with vDISCO.
  26. Mechanically primed cells transfer memory to fibrous matrices for invasion across environments of distinct stiffness and dimensionality.
  27. Cellular Invasion Assay for the Real-Time Tracking of Individual Cells in Spheroid or Tumor-like Mimics.
  28. Albert Reynolds (1956-2022): The father of p120.
  29. Mechanisms of cancer pain.
  30. Protein therapy of skeletal muscle atrophy and mechanism by angiogenic factor AGGF1.
  31. Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS.
  32. Overall Survival With Adjuvant mFOLFIRINOX for Pancreatic Cancer-Reply.
  33. Overall Survival With Adjuvant mFOLFIRINOX for Pancreatic Cancer.
  34. Metabolism, homeostasis, and aging.
  35. The KRAS crowd targets its next cancer mutations.
  1. Cell Metab. 2023 Jan 14. pii: S1550-4131(22)00577-0. [Epub ahead of print]
    Isolation of extracellular fluids reveals novel secreted bioactive proteins from muscle and fat tissues.
    Melanie J Mittenbühler, Mark P Jedrychowski, Jonathan G Van Vranken, Hans-Georg Sprenger, Sarah Wilensky, Phillip A Dumesic, Yizhi Sun, Andrea Tartaglia, Dina Bogoslavski, Mu A, Haopeng Xiao, Katherine A Blackmore, Anita Reddy, Steven P Gygi, Edward T Chouchani, Bruce M Spiegelman.
      Proteins are secreted from cells to send information to neighboring cells or distant tissues. Because of the highly integrated nature of energy balance systems, there has been particular interest in myokines and adipokines. These are challenging to study through proteomics because serum or plasma contains highly abundant proteins that limit the detection of proteins with lower abundance. We show here that extracellular fluid (EF) from muscle and fat tissues of mice shows a different protein composition than either serum or tissues. Mass spectrometry analyses of EFs from mice with physiological perturbations, like exercise or cold exposure, allowed the quantification of many potentially novel myokines and adipokines. Using this approach, we identify prosaposin as a secreted product of muscle and fat. Prosaposin expression stimulates thermogenic gene expression and induces mitochondrial respiration in primary fat cells. These studies together illustrate the utility of EF isolation as a discovery tool for adipokines and myokines.
    Keywords:  PGC1α; cold adaptation; exercise; extracellular fluid; prosaposin; proteomics; secreted proteins; secretome
    DOI:  https://doi.org/10.1016/j.cmet.2022.12.014
  2. Cell Death Dis. 2023 Jan 26. 14(1): 61
    Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors.
    Vrushank Bhatt, Taijin Lan, Wenping Wang, Jerry Kong, Eduardo Cararo Lopes, Jianming Wang, Khoosheh Khayati, Akash Raju, Michael Rangel, Enrique Lopez, Zhixian Sherrie Hu, Xuefei Luo, Xiaoyang Su, Jyoti Malhotra, Wenwei Hu, Sharon R Pine, Eileen White, Jessie Yanxiang Guo.
      LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung cancer (NSCLC) and cause aggressive tumor growth. Unfortunately, treatment with RAS-RAF-MEK-ERK pathway inhibitors has minimal therapeutic efficacy in LKB1-mutant KRAS-driven NSCLC. Autophagy, an intracellular nutrient scavenging pathway, compensates for Lkb1 loss to support Kras-driven lung tumor growth. Here we preclinically evaluate the possibility of autophagy inhibition together with MEK inhibition as a treatment for Kras-driven lung tumors. We found that the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and the MEK inhibitor Trametinib displays synergistic anti-proliferative activity in KrasG12D/+;Lkb1-/- (KL) lung cancer cells, but not in KrasG12D/+;p53-/- (KP) lung cancer cells. In vivo studies using tumor allografts, genetically engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) showed anti-tumor activity of the combination of HCQ and Trametinib on KL but not KP tumors. We further found that the combination treatment significantly reduced mitochondrial membrane potential, basal respiration, and ATP production, while also increasing lipid peroxidation, indicative of ferroptosis, in KL tumor-derived cell lines (TDCLs) and KL tumors compared to treatment with single agents. Moreover, the reduced tumor growth by the combination treatment was rescued by ferroptosis inhibitor. Taken together, we demonstrate that autophagy upregulation in KL tumors causes resistance to Trametinib by inhibiting ferroptosis. Therefore, a combination of autophagy and MEK inhibition could be a novel therapeutic strategy to specifically treat NSCLC bearing co-mutations of LKB1 and KRAS.
    DOI:  https://doi.org/10.1038/s41419-023-05592-8
  3. Life Med. 2022 Oct;1(2): 103-119
    Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging.
    Yu Sun, Qingfeng Li, James L Kirkland.
      Aging is a natural but relentless process of physiological decline, leading to physical frailty, reduced ability to respond to physical stresses (resilience) and, ultimately, organismal death. Cellular senescence, a self-defensive mechanism activated in response to intrinsic stimuli and/or exogenous stress, is one of the central hallmarks of aging. Senescent cells cease to proliferate, while remaining metabolically active and secreting numerous extracellular factors, a feature known as the senescence-associated secretory phenotype. Senescence is physiologically important for embryonic development, tissue repair, and wound healing, and prevents carcinogenesis. However, chronic accumulation of persisting senescent cells contributes to a host of pathologies including age-related morbidities. By paracrine and endocrine mechanisms, senescent cells can induce inflammation locally and systemically, thereby causing tissue dysfunction, and organ degeneration. Agents including those targeting damaging components of the senescence-associated secretory phenotype or inducing apoptosis of senescent cells exhibit remarkable benefits in both preclinical models and early clinical trials for geriatric conditions. Here we summarize features of senescent cells and outline strategies holding the potential to be developed as clinical interventions. In the long run, there is an increasing demand for safe, effective, and clinically translatable senotherapeutics to address healthcare needs in current settings of global aging.
    Keywords:  aging; clinical trial; senescence-associated secretory phenotype; senescent cell; senotherapeutics
    DOI:  https://doi.org/10.1093/lifemedi/lnac030
  4. Cell Rep. 2023 Jan 25. pii: S2211-1247(23)00048-7. [Epub ahead of print]42(2): 112037
    The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy.
    Elizabeth R Gallagher, Erika L F Holzbaur.
      In response to lysosomal damage, cells engage several quality-control mechanisms, including the selective isolation and degradation of damaged lysosomes by lysophagy. Here, we report that the selective autophagy adaptor SQSTM1/p62 is recruited to damaged lysosomes in both HeLa cells and neurons and is required for lysophagic flux. The Phox and Bem1p (PB1) domain of p62 mediates oligomerization and is specifically required for lysophagy. Consistent with this observation, we find that p62 forms condensates on damaged lysosomes. These condensates are precisely tuned by the small heat shock protein HSP27, which is phosphorylated in response to lysosomal injury and maintains the liquidity of p62 condensates, facilitating autophagosome formation. Mutations in p62 have been identified in patients with amyotrophic lateral sclerosis (ALS); ALS-associated mutations in p62 impair lysophagy, suggesting that deficits in this pathway may contribute to neurodegeneration. Thus, p62 condensates regulated by HSP27 promote lysophagy by forming platforms for autophagosome biogenesis at damaged lysosomes.
    Keywords:  ALS; CP: Cell biology; CP: Neuroscience; HSP27; autophagy; condensates; lysophagy; lysosome; neurodegeneration; neurons; p62/SQSTM1; phase separation
    DOI:  https://doi.org/10.1016/j.celrep.2023.112037
  5. Lab Anim (NY). 2023 Jan 24.
    Investigating trajectories of aging using high-dimensional phenotyping in mice.
    Michael R MacArthur, Sarah J Mitchell.
      
    DOI:  https://doi.org/10.1038/s41684-023-01122-3
  6. Nature. 2023 Jan 25.
    A census of complexes formed by mitochondrial proteins.
      
    Keywords:  Biochemistry; Cell biology; Metabolism; Proteomics
    DOI:  https://doi.org/10.1038/d41586-023-00095-0
  7. Sci Adv. 2023 Jan 25. 9(4): eadd0636
    Characterization of proteome-size scaling by integrative omics reveals mechanisms of proliferation control in cancer.
    Ian Jones, Lucas Dent, Tomoaki Higo, Theodoros Roumeliotis, Maria Arias Garcia, Hansa Shree, Jyoti Choudhary, Malin Pedersen, Chris Bakal.
      Almost all living cells maintain size uniformity through successive divisions. Proteins that over and underscale with size can act as rheostats, which regulate cell cycle progression. Using a multiomic strategy, we leveraged the heterogeneity of melanoma cell lines to identify peptides, transcripts, and phosphorylation events that differentially scale with cell size. Subscaling proteins are enriched in regulators of the DNA damage response and cell cycle progression, whereas super-scaling proteins included regulators of the cytoskeleton, extracellular matrix, and inflammatory response. Mathematical modeling suggested that decoupling growth and proliferative signaling may facilitate cell cycle entry over senescence in large cells when mitogenic signaling is decreased. Regression analysis reveals that up-regulation of TP53 or CDKN1A/p21CIP1 is characteristic of proliferative cancer cells with senescent-like sizes/proteomes. This study provides one of the first demonstrations of size-scaling phenomena in cancer and how morphology influences the chemistry of the cell.
    DOI:  https://doi.org/10.1126/sciadv.add0636
  8. Cell. 2023 Jan 19. pii: S0092-8674(22)01579-3. [Epub ahead of print]
    Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication.
    Jingkun Zeng, Stephanie A Hills, Eiko Ozono, John F X Diffley.
      Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneuploidy. The role of the p53 tumor suppressor in WGD has been enigmatic: p53 can block the proliferation of tetraploid cells, acting as a barrier to WGD, but can also promote mitotic bypass, a key step in WGD via endoreduplication. In wild-type (WT) p53 tumors, WGD is frequently associated with activation of the E2F pathway, especially amplification of CCNE1, encoding cyclin E1. Here, we show that elevated cyclin E1 expression causes replicative stress, which activates ATR- and Chk1-dependent G2 phase arrest. p53, via its downstream target p21, together with Wee1, then inhibits mitotic cyclin-dependent kinase activity sufficiently to activate APC/CCdh1 and promote mitotic bypass. Cyclin E expression suppresses p53-dependent senescence after mitotic bypass, allowing cells to complete endoreduplication. Our results indicate that p53 can contribute to cancer evolution through the promotion of WGD.
    Keywords:  DNA replication; aneuploidy; cancer biology; cell cycle; cyclin E; mitotic bypass; whole-genome duplication
    DOI:  https://doi.org/10.1016/j.cell.2022.12.036
  9. EMBO Mol Med. 2023 Jan 26. e15914
    The molecular biology of peritoneal metastatic disease.
    Sanne Bootsma, Maarten F Bijlsma, Louis Vermeulen.
      Peritoneal metastases are a common form of tumor cell dissemination in gastrointestinal malignancies. Peritoneal metastatic disease (PMD) is associated with severe morbidity and resistance to currently employed therapies. Given the distinct route of dissemination compared with distant organ metastases, and the unique microenvironment of the peritoneal cavity, specific tumor cell characteristics are needed for the development of PMD. In this review, we provide an overview of the known histopathological, genomic, and transcriptomic features of PMD. We find that cancers representing the mesenchymal subtype are strongly associated with PMD in various malignancies. Furthermore, we discuss the peritoneal niche in which the metastatic cancer cells reside, including the critical role of the peritoneal immune system. Altogether, we show that PMD should be regarded as a distinct disease entity, that requires tailored treatment strategies.
    Keywords:  gastrointestinal cancer; metastasis; peritoneum; tumor biology; tumor microenvironment
    DOI:  https://doi.org/10.15252/emmm.202215914
  10. Front Oncol. 2022 ;12 1007134
    Multitasking dynamic contrast enhanced magnetic resonance imaging can accurately differentiate chronic pancreatitis from pancreatic ductal adenocarcinoma.
    Nan Wang, Srinivas Gaddam, Yibin Xie, Anthony G Christodoulou, Chaowei Wu, Sen Ma, Zhaoyang Fan, Lixia Wang, Simon Lo, Andrew E Hendifar, Stephen J Pandol, Debiao Li.
      Background and aims: Accurate differentiation of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) is an area of unmet clinical need. In this study, a novel Multitasking dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) technique was used to quantitatively evaluate the microcirculation properties of pancreas in CP and PDAC and differentiate between them.Methods: The Multitasking DCE technique was able to acquire one 3D image per second during the passage of MRI contrast agent, allowing the quantitative estimation of microcirculation properties of tissue, including blood flow Fp, plasma volume fraction vp, transfer constant Ktrans, and extravascular extracellular volume fraction ve. Receiver operating characteristic (ROC) analysis was performed to differentiate the CP pancreas, PDAC pancreas, normal control pancreas, PDAC tumor, PDAC upstream, and PDAC downstream. ROCs from quantitative analysis and conventional analysis were compared.
    Results: Fourteen PDAC patients, 8 CP patients and 20 healthy subjects were prospectively recruited. The combination of Fp, vp, Ktrans, and ve can differentiate CP versus PDAC pancreas with good AUC (AUC [95% CI] = 0.821 [0.654 - 0.988]), CP versus normal pancreas with excellent AUC (1.000 [1.000 - 1.000]), PDAC pancreas versus normal pancreas with excellent AUC (1.000 [1.000 - 1.000]), CP versus PDAC tumor with excellent AUC (1.000 [1.000 - 1.000]), CP versus PDAC downstream with excellent AUC (0.917 [0.795 - 1.000]), and CP versus PDAC upstream with fair AUC (0.722 [0.465 - 0.980]). This quantitative analysis outperformed conventional analysis in differentiation of each pair.
    Conclusion: Multitasking DCE MRI is a promising clinical tool that is capable of unbiased quantitative differentiation between CP from PDAC.
    Keywords:  Multitasking DCE; differential diagnosis of chronic pancreatitis and pancreatic ductal adenocarcinoma; dynamic contrast enhanced magnetic resonance imaging; microcirculation properties; quantitative imaging
    DOI:  https://doi.org/10.3389/fonc.2022.1007134
  11. J Biol Chem. 2023 Jan 18. pii: S0021-9258(23)00055-8. [Epub ahead of print] 102923
    Comprehensive characterization of complex glycosphingolipids in human pancreatic cancer tissues.
    Karel Hořejší, Chunsheng Jin, Zuzana Vaňková, Robert Jirásko, Ondřej Strouhal, Bohuslav Melichar, Susann Teneberg, Michal Holčapek.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer-related deaths worldwide, accounting for 90% of primary pancreatic tumors with an average 5-year survival rate of less than 10%. PDAC exhibits aggressive biology, which, together with late detection, results in most PDAC patients presenting with unresectable, locally advanced, or metastatic disease. In-depth lipid profiling and screening of potential biomarkers currently appear to be a promising approach for early detection of PDAC or other cancers. Here, we isolated and characterized complex glycosphingolipids (GSL) from normal and tumor pancreatic tissues of patients with PDAC using a combination of thin-layer chromatography, chemical staining, carbohydrate-recognized ligand binding assay, and LC/ESI-MS2. The major neutral GSL identified were GSL with the terminal blood groups A, B, H, Lea, Leb, Lex, Ley, P1, and PX2 determinants together with globo- (Gb3 and Gb4), and neolacto-series GSL (nLc4 and nLc6). We also revealed that the neutral GSL profiles and their relative amounts differ between normal and tumor tissues. Additionally, the normal and tumor pancreatic tissues differ in type 1/2 core chains. Sulfatides and GM3 gangliosides were the predominant acidic GSL along with the minor sialyl-nLc4/nLc6 and sialyl-Lea/Lex. The comprehensive analysis of GSL in human PDAC tissues extends the GSL coverage and provides an important platform for further studies of GSL alterations; therefore, it could contribute to the development of new biomarkers and therapeutic approaches.
    Keywords:  Chromatogram Binding Assay; Glycolipids; Lipidomics; Lipids; Liquid Chromatography; Monoclonal antibodies; Pancreatic Cancer; Sphingolipids; Tandem Mass Spectrometry; Thin-layer Chromatography
    DOI:  https://doi.org/10.1016/j.jbc.2023.102923
  12. Nature. 2023 Jan 25.
    Mitochondrial complexome reveals quality-control pathways of protein import.
    Uwe Schulte, Fabian den Brave, Alexander Haupt, Arushi Gupta, Jiyao Song, Catrin S Müller, Jeannine Engelke, Swadha Mishra, Christoph Mårtensson, Lars Ellenrieder, Chantal Priesnitz, Sebastian P Straub, Kim Nguyen Doan, Bogusz Kulawiak, Wolfgang Bildl, Heike Rampelt, Nils Wiedemann, Nikolaus Pfanner, Bernd Fakler, Thomas Becker.
      Mitochondria have crucial roles in cellular energetics, metabolism, signalling and quality control1-4. They contain around 1,000 different proteins that often assemble into complexes and supercomplexes such as respiratory complexes and preprotein translocases1,3-7. The composition of the mitochondrial proteome has been characterized1,3,5,6; however, the organization of mitochondrial proteins into stable and dynamic assemblies is poorly understood for major parts of the proteome1,4,7. Here we report quantitative mapping of mitochondrial protein assemblies using high-resolution complexome profiling of more than 90% of the yeast mitochondrial proteome, termed MitCOM. An analysis of the MitCOM dataset resolves >5,200 protein peaks with an average of six peaks per protein and demonstrates a notable complexity of mitochondrial protein assemblies with distinct appearance for respiration, metabolism, biogenesis, dynamics, regulation and redox processes. We detect interactors of the mitochondrial receptor for cytosolic ribosomes, of prohibitin scaffolds and of respiratory complexes. The identification of quality-control factors operating at the mitochondrial protein entry gate reveals pathways for preprotein ubiquitylation, deubiquitylation and degradation. Interactions between the peptidyl-tRNA hydrolase Pth2 and the entry gate led to the elucidation of a constitutive pathway for the removal of preproteins. The MitCOM dataset-which is accessible through an interactive profile viewer-is a comprehensive resource for the identification, organization and interaction of mitochondrial machineries and pathways.
    DOI:  https://doi.org/10.1038/s41586-022-05641-w
  13. Autophagy. 2023 Jan 24.
    Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination.
    Ayesha Sen, Julia Boix, David Pla-Martín.
      Mitophagy and its variants are considered important salvage pathways to remove dysfunctional mitochondria. Non-canonical mitophagy, independent of autophagosome formation and including endosomal-dependent mitophagy, operate upon specific injury. In a recent paper, we describe a new mechanism where, upon mtDNA damage, mitochondrial nucleoids are eliminated via an endosomal-mitophagy pathway. Using proximity proteomics, we identified the proteins required for elimination of mutated mitochondrial nucleoids from the mitochondrial matrix. Among them, ATAD3 and SAMM50 control cristae architecture and nucleoid interaction, necessary for mtDNA extraction. In the mitochondrial outer membrane, SAMM50 coordinates with the retromer protein VPS35 to sequester mtDNA in endosomes and guide them towards elimination, thus avoiding the activation of an exacerbated immune response. Here, we summarize our findings and examine how this newly described pathway contributes to our understanding of mtDNA quality control.
    Keywords:  - mitophagy; endosomes; mtDNA
    DOI:  https://doi.org/10.1080/15548627.2023.2170959
  14. Cancer Cell. 2023 Jan 19. pii: S1535-6108(23)00002-8. [Epub ahead of print]
    Neutrophil-activating therapy for the treatment of cancer.
    Ian L Linde, Tyler R Prestwood, Jingtao Qiu, Genay Pilarowski, Miles H Linde, Xiangyue Zhang, Lei Shen, Nathan E Reticker-Flynn, David Kung-Chun Chiu, Lauren Y Sheu, Simon Van Deursen, Lorna L Tolentino, Wen-Chao Song, Edgar G Engleman.
      Despite their cytotoxic capacity, neutrophils are often co-opted by cancers to promote immunosuppression, tumor growth, and metastasis. Consequently, these cells have received little attention as potential cancer immunotherapeutic agents. Here, we demonstrate in mouse models that neutrophils can be harnessed to induce eradication of tumors and reduce metastatic seeding through the combined actions of tumor necrosis factor, CD40 agonist, and tumor-binding antibody. The same combination activates human neutrophils in vitro, enabling their lysis of human tumor cells. Mechanistically, this therapy induces rapid mobilization and tumor infiltration of neutrophils along with complement activation in tumors. Complement component C5a activates neutrophils to produce leukotriene B4, which stimulates reactive oxygen species production via xanthine oxidase, resulting in oxidative damage and T cell-independent clearance of multiple tumor types. These data establish neutrophils as potent anti-tumor immune mediators and define an inflammatory pathway that can be harnessed to drive neutrophil-mediated eradication of cancer.
    Keywords:  C5a; CD40; cancer immunotherapy; complement; leukotriene B4; neutrophil; reactive oxygen species; tumor immunology; tumor necrosis factor; xanthine oxidase
    DOI:  https://doi.org/10.1016/j.ccell.2023.01.002
  15. Cancer Metastasis Rev. 2023 Jan 21.
    Insights into the role of senescence in tumor dormancy: mechanisms and applications.
    Valerie J DeLuca, Tareq Saleh.
      One of the most formidable challenges in oncology and tumor biology research is to provide an accurate understanding of tumor dormancy mechanisms. Dormancy refers to the ability of tumor cells to go undetected in the body for a prolonged period, followed by "spontaneous" escape. Various models of dormancy have been postulated, including angiogenic, immune-mediated, and cellular dormancy. While the former two propose mechanisms by which tumor growth may remain static at a population level, cellular dormancy refers to molecular processes that restrict proliferation at the cell level. Senescence is a form of growth arrest, during which cells undergo distinct phenotypic, epigenetic, and metabolic changes. Senescence is also associated with the development of a robust secretome, comprised of various chemokines and cytokines that interact with the surrounding microenvironment, including other tumor cells, stromal cells, endothelial cells, and immune cells. Both tumor and non-tumor cells can undergo senescence following various stressors, many of which are present during tumorigenesis and therapy. As such, senescent cells are present within forming tumors and in residual tumors post-treatment and therefore play a major role in tumor biology. However, the contributions of senescence to dormancy are largely understudied. Here, we provide an overview of multiple processes that have been well established as being involved in tumor dormancy, and we speculate on how senescence may contribute to these mechanisms.
    Keywords:  Angiogenic; Autophagy; Cancer; Dormancy; Immunogenic; Polyploidy; Recurrence; Senescence
    DOI:  https://doi.org/10.1007/s10555-023-10082-6
  16. Cancer Metastasis Rev. 2023 Jan 26.
    Involvement of redox signalling in tumour cell dormancy and metastasis.
    Beatriz Puente-Cobacho, Alfonso Varela-López, José L Quiles, Laura Vera-Ramirez.
      Decades of research on oncogene-driven carcinogenesis and gene-expression regulatory networks only started to unveil the complexity of tumour cellular and molecular biology. This knowledge has been successfully implemented in the clinical practice to treat primary tumours. In contrast, much less progress has been made in the development of new therapies against metastasis, which are the main cause of cancer-related deaths. More recently, the role of epigenetic and microenviromental factors has been shown to play a key role in tumour progression. Free radicals are known to communicate the intracellular and extracellular compartments, acting as second messengers and exerting a decisive modulatory effect on tumour cell signalling. Depending on the cellular and molecular context, as well as the intracellular concentration of free radicals and the activation status of the antioxidant system of the cell, the signalling equilibrium can be tilted either towards tumour cell survival and progression or cell death. In this regard, recent advances in tumour cell biology and metastasis indicate that redox signalling is at the base of many cell-intrinsic and microenvironmental mechanisms that control disseminated tumour cell fate and metastasis. In this manuscript, we will review the current knowledge about redox signalling along the different phases of the metastatic cascade, including tumour cell dormancy, making emphasis on metabolism and the establishment of supportive microenvironmental connections, from a redox perspective.
    Keywords:  Metastasis; Oxidative stress; Redox signalling; Tumour cell dormancy
    DOI:  https://doi.org/10.1007/s10555-022-10077-9
  17. J Biol Chem. 2023 Jan 21. pii: S0021-9258(23)00067-4. [Epub ahead of print] 102935
    The role of glycans in the mechanobiology of cancer.
    Anurag Purushothaman, Mohammad Mohajeri, Tanmay P Lele.
      Although cancer is a genetic disease, physical changes such as stiffening of the extracellular matrix (ECM) also commonly occur in cancer. Cancer cells sense and respond to ECM stiffening through the process of mechanotransduction. Cancer cell mechanotransduction can enhance cancer-promoting cell behaviors such as survival signaling, proliferation, and migration. Glycans, carbohydrate-based polymers, have recently emerged as important mediators and/or modulators of cancer cell mechanotransduction. Stiffer tumors are characterized by increased glycan content on cancer cells and their associated extracellular matrix. Here we review the role of cancer- associated glycans in coupled mechanical and biochemical alterations during cancer progression. We discuss the recent evidence on how increased expression of different glycans, in the form of glycoproteins and proteoglycans, contributes to both mechanical changes in tumors and corresponding cancer cell responses. We conclude with a summary of emerging tools that can be used to modify glycans for future studies in cancer mechanobiology.
    Keywords:  cancer; collagen; glycans; mechanobiology; proteoglycans
    DOI:  https://doi.org/10.1016/j.jbc.2023.102935
  18. Aging Cell. 2023 Jan 23. e13783
    Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis.
    Jianrui Song, Diana Farris, Paola Ariza, Smriti Moorjani, Mita Varghese, Muriel Blin, Judy Chen, Daniel Tyrrell, Min Zhang, Kanakadurga Singer, Morgan Salmon, Daniel R Goldstein.
      Although aging enhances atherosclerosis, we do not know if this occurs via alterations in circulating immune cells, lipid metabolism, vasculature, or adipose tissue. Here, we examined whether aging exerts a direct pro-atherogenic effect on adipose tissue in mice. After demonstrating that aging augmented the inflammatory profile of visceral but not subcutaneous adipose tissue, we transplanted visceral fat from young or aged mice onto the right carotid artery of Ldlr-/- recipients. Aged fat transplants not only increased atherosclerotic plaque size with increased macrophage numbers in the adjacent carotid artery, but also in distal vascular territories, indicating that aging of the adipose tissue enhances atherosclerosis via secreted factors. By depleting macrophages from the visceral fat, we identified that adipose tissue macrophages are major contributors of the secreted factors. To identify these inflammatory factors, we found that aged fat transplants secreted increased levels of the inflammatory mediators TNFα, CXCL2, and CCL2, which synergized to promote monocyte chemotaxis. Importantly, the combined blockade of these inflammatory mediators impeded the ability of aged fat transplants to enhance atherosclerosis. In conclusion, our study reveals that aging enhances atherosclerosis via increased inflammation of visceral fat. Our study suggests that future therapies targeting the visceral fat may reduce atherosclerosis disease burden in the expanding older population.
    Keywords:  atherosclerosis; inflammation; macrophage; monocyte; visceral adipose tissue
    DOI:  https://doi.org/10.1111/acel.13783
  19. Ann Surg Oncol. 2023 Jan 24.
    Reappraisal of Tumor Deposit as a Prognostic Factor in Pancreatic Cancer.
    Jie Hua, Jin Xu, Chen Liang, Qingcai Meng, Bo Zhang, Xianjun Yu, Wei Wang, Si Shi.
      PURPOSE: Tumor deposits (TDs) are discrete tumor nodules within the lymphatic drainage area of the primary tumor without histological evidence of lymph node tissue or identifiable vascular or neural structure. This study aims to analyze the prognostic impact of TDs in patients with pancreatic ductal adenocarcinoma (PDAC) and explore their potential role in staging system.METHODS: The prospectively maintained database from the Fudan University Shanghai Cancer Center was queried for patients undergoing resection for PDAC. Patients with TDs were matched by propensity score with those without TDs. The cumulative prevalence of recurrence was estimated using the cumulative incidence function. Overall survival was estimated using Kaplan-Meier curves.
    RESULTS: A total of 123 patients (9.7%) had TDs, of whom 108 were matched at a 1:3 ratio with 324 patients without TDs. The cumulative incidence of recurrence was significantly higher for TD-positive patients than TD-negative patients (P = 0.04). The median overall survival was significantly shorter for patients with TDs than for those without TDs (15.9 versus 21.8 months, P < 0.001). The presence of TDs attenuated the effect of lymph node metastasis on survival, with no significance between node-negative and node-positive subpopulations (P = 0.165). Patients with TDs had comparable survival to N2 patients without TDs (15.9 versus 17.1 months, P = 0.383).
    CONCLUSIONS: TD is an important prognostic factor for recurrence and survival in patients undergoing resection for PDAC. We suggest that patients presenting TDs be classified into the stage III category in the next edition of the staging system.
    DOI:  https://doi.org/10.1245/s10434-023-13102-5
  20. Autophagy. 2023 Jan 24. 1-18
    Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules.
    Cuiwei Yang, Zhangshun Wang, Yingjin Kang, Qianqian Yi, Tong Wang, Yun Bai, Yanfen Liu.
      Eukaryotic stress granules (SGs) are highly dynamic assemblies of untranslated mRNAs and proteins that form through liquid-liquid phase separation (LLPS) under cellular stress. SG formation and elimination process is a conserved cellular strategy to promote cell survival, although the precise regulation of this process is poorly understood. Here, we screened six E3 ubiquitin ligases present in SGs and identified TRIM21 (tripartite motif containing 21) as a central regulator of SG homeostasis that is highly enriched in SGs of cells under arsenite-induced oxidative stress. Knockdown of TRIM21 promotes SG formation whereas overexpression of TRIM21 inhibits the formation of physiological and pathological SGs associated with neurodegenerative diseases. TRIM21 catalyzes K63-linked ubiquitination of the SG core protein, G3BP1 (G3BP stress granule assembly factor 1), and G3BP1 ubiquitination can effectively inhibit LLPS, in vitro. Recent reports suggested the involvement of macroautophagy/autophagy, as a stress response pathway, in the regulation of SG homeostasis. We systematically investigated well-defined autophagy receptors and identified SQSTM1/p62 (sequestosome 1) and CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2) as the primary receptors that directly interact with G3BP1 during arsenite-induced stress. Endogenous SQSTM1 and CALCOCO2 localize to the periphery of SGs under oxidative stress and mediate SG elimination, as single knockout of each receptor causes accumulation of physiological and pathological SGs. Collectively, our study broadens the understanding in the regulation of SG homeostasis by showing that TRIM21 and autophagy receptors modulate SG formation and elimination respectively, suggesting the possibility of clinical targeting of these molecules in therapeutic strategies for neurodegenerative diseases.Abbreviations: ACTB: actin beta; ALS: amyotrophic lateral sclerosis; BafA1: bafilomycin A1; BECN1: beclin 1; C9orf72: C9orf72-SMCR8 complex subunit; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; Co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2-phenylindole; FTD: frontotemporal dementia; FUS: FUS RNA binding protein; G3BP1: G3BP stress granule assembly factor 1; GFP: green fluorescent protein; LLPS: liquid-liquid phase separation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NBR1: NBR1 autophagy cargo receptor; NES: nuclear export signal; OPTN: optineurin; RFP: red fluorescent protein; SQSTM1/p62: sequestosome 1; SG: stress granule; TAX1BP1: Tax1 binding protein 1; TOLLIP: toll interacting protein; TRIM21: tripartite motif containing 21; TRIM56: tripartite motif containing 56; UB: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.
    Keywords:  Autophagy receptor; CALCOCO2; G3BP1; SQSTM1; TRIM21; stress granule; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2022.2164427
  21. EMBO J. 2023 Jan 27. e112309
    MitoStores: chaperone-controlled protein granules store mitochondrial precursors in the cytosol.
    Lena Krämer, Niko Dalheimer, Markus Räschle, Zuzana Storchová, Jan Pielage, Felix Boos, Johannes M Herrmann.
      Hundreds of nucleus-encoded mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational manner. However, the early processes associated with mitochondrial protein targeting remain poorly understood. Here, we show that in Saccharomyces cerevisiae, the cytosol has the capacity to transiently store mitochondrial matrix-destined precursors in dedicated deposits that we termed MitoStores. Competitive inhibition of mitochondrial protein import via clogging of import sites greatly enhances the formation of MitoStores, but they also form during physiological cell growth on nonfermentable carbon sources. MitoStores are enriched for a specific subset of nucleus-encoded mitochondrial proteins, in particular those containing N-terminal mitochondrial targeting sequences. Our results suggest that MitoStore formation suppresses the toxic potential of aberrantly accumulating mitochondrial precursor proteins and is controlled by the heat shock proteins Hsp42 and Hsp104. Thus, the cytosolic protein quality control system plays an active role during the early stages of mitochondrial protein targeting through the coordinated and localized sequestration of mitochondrial precursor proteins.
    Keywords:  chaperones; mitochondria; proteasome; protein aggregates; protein translocation
    DOI:  https://doi.org/10.15252/embj.2022112309
  22. Science. 2023 Jan 27. eabj9090
    Exon architecture controls mRNA m6A suppression and gene expression.
    P Cody He, Jiangbo Wei, Xiaoyang Dou, Bryan T Harada, Zijie Zhang, Ruiqi Ge, Chang Liu, Li-Sheng Zhang, Xianbin Yu, Shuai Wang, Ruitu Lyu, Zhongyu Zou, Mengjie Chen, Chuan He.
      N6-methyladenosine (m6A) is the most abundant mRNA modification and plays crucial roles in diverse physiological processes. Utilizing a Massively Parallel Assay for m6A (MPm6A), we discover that m6A specificity is globally regulated by "suppressors" that prevent m6A deposition in unmethylated transcriptome regions. We identify Exon Junction Complexes (EJCs) as m6A suppressors that protect exon junction-proximal RNA within coding sequences from methylation and regulate mRNA stability through m6A suppression. EJC suppression of m6A underlies multiple global characteristics of mRNA m6A specificity, with the local range of EJC protection sufficient to suppress m6A deposition in average-length internal exons, but not in long internal and terminal exons. EJC-suppressed methylation sites co-localize with EJC-suppressed splice sites, suggesting that exon architecture broadly determines local mRNA accessibility to regulatory complexes.
    DOI:  https://doi.org/10.1126/science.abj9090
  23. Mol Syst Biol. 2023 Jan 23. e10631
    Pan-Cancer landscape of protein activities identifies drivers of signalling dysregulation and patient survival.
    Abel Sousa, Aurelien Dugourd, Danish Memon, Borgthor Petursson, Evangelia Petsalaki, Julio Saez-Rodriguez, Pedro Beltrao.
      Genetic alterations in cancer cells trigger oncogenic transformation, a process largely mediated by the dysregulation of kinase and transcription factor (TF) activities. While the mutational profiles of thousands of tumours have been extensively characterised, the measurements of protein activities have been technically limited until recently. We compiled public data of matched genomics and (phospho)proteomics measurements for 1,110 tumours and 77 cell lines that we used to estimate activity changes in 218 kinases and 292 TFs. Co-regulation of kinase and TF activities reflects previously known regulatory relationships and allows us to dissect genetic drivers of signalling changes in cancer. We find that loss-of-function mutations are not often associated with the dysregulation of downstream targets, suggesting frequent compensatory mechanisms. Finally, we identified the activities most differentially regulated in cancer subtypes and showed how these can be linked to differences in patient survival. Our results provide broad insights into the dysregulation of protein activities in cancer and their contribution to disease severity.
    Keywords:  adaptation; cancer genomics; cell signalling; phosphoproteomics; protein activities
    DOI:  https://doi.org/10.15252/msb.202110631
  24. Anticancer Res. 2023 Feb;43(2): 511-521
    The Latest Treatments for Cancer Cachexia: An Overview.
    Hayato Watanabe, Takashi Oshima.
      Cancer cachexia demonstrates the same pathology as cachexia found in patients with disease-associated malnutrition presenting with inflammation. In advanced cancer, a decrease in skeletal muscle mass progresses with an increase in cancer cell mass. Moreover, cancer cachexia causes systemic edema and cachexia, reduces the efficacy of chemotherapy, and negatively affects cancer prognosis. Early nutritional intervention and multidisciplinary care are essential to ensure sufficient nutritional requirements and minimize anabolic resistance factors. In addition, preventive care that minimizes deterioration of nutritional status and loss of skeletal muscle mass is required for the effective treatment of cachexia. Therefore, the current review sought to comprehensively describe the available evidence for the effective pharmaceutical treatment of cancer-associated cachexia. Steroids have traditionally been used for cachexia drug therapy. However, their effects are limited, and it is difficult to radically restore the highly reduced muscle mass inherent to cancer-associated cachexia. Recently, anamorelin hydrochloride, an endogenous ligand for the growth hormone release-promoting factor receptor, which has a similar pharmacological action to that of ghrelin, was developed to treat weight loss accompanied by anorexia. This medication also treats cachexia and was the first drug to be approved for this purpose. Anamorelin hydrochloride is expected to bring new advancements into the field of clinical oncology as an effective therapeutic drug for cancer cachexia, a devastating complication that, so far, has no definitive and effective treatment.
    Keywords:  Cancer cachexia; anamorelin hydrochloride; review
    DOI:  https://doi.org/10.21873/anticanres.16188
  25. Nat Protoc. 2023 Jan 25.
    Whole-mouse clearing and imaging at the cellular level with vDISCO.
    Ruiyao Cai, Zeynep Ilgin Kolabas, Chenchen Pan, Hongcheng Mai, Shan Zhao, Doris Kaltenecker, Fabian F Voigt, Muge Molbay, Tzu-Lun Ohn, Cécile Vincke, Mihail I Todorov, Fritjof Helmchen, Jo A Van Ginderachter, Ali Ertürk.
      Homeostatic and pathological phenomena often affect multiple organs across the whole organism. Tissue clearing methods, together with recent advances in microscopy, have made holistic examinations of biological samples feasible. Here, we report the detailed protocol for nanobody(VHH)-boosted 3D imaging of solvent-cleared organs (vDISCO), a pressure-driven, nanobody-based whole-body immunolabeling and clearing method that renders whole mice transparent in 3 weeks, consistently enhancing the signal of fluorescent proteins, stabilizing them for years. This allows the reliable detection and quantification of fluorescent signal in intact rodents enabling the analysis of an entire body at cellular resolution. Here, we show the high versatility of vDISCO applied to boost the fluorescence signal of genetically expressed reporters and clear multiple dissected organs and tissues, as well as how to image processed samples using multiple fluorescence microscopy systems. The entire protocol is accessible to laboratories with limited expertise in tissue clearing. In addition to its applications in obtaining a whole-mouse neuronal projection map, detecting single-cell metastases in whole mice and identifying previously undescribed anatomical structures, we further show the visualization of the entire mouse lymphatic system, the application for virus tracing and the visualization of all pericytes in the brain. Taken together, our vDISCO pipeline allows systematic and comprehensive studies of cellular phenomena and connectivity in whole bodies.
    DOI:  https://doi.org/10.1038/s41596-022-00788-2
  26. Mol Biol Cell. 2023 Jan 25. mbcE22100469
    Mechanically primed cells transfer memory to fibrous matrices for invasion across environments of distinct stiffness and dimensionality.
    José Almeida, Jairaj Mathur, Ye Lim Lee, Bapi Sarker, Amit Pathak.
      Cells sense and migrate across mechanically dissimilar environments throughout development and disease progression. However, it remains unclear whether mechanical memory of past environments empowers cells to navigate new, three-dimensional extracellular matrices. Here, we show that cells previously primed on stiff matrices, compared to soft, generate higher forces to remodel collagen fibers and promote invasion. This priming advantage persists in dense or stiffened collagen. We explain this memory-dependent cross-environment cell invasion through a lattice-based model wherein stiff-primed cellular forces remodel collagen and minimize energy required for future cell invasion. According to our model, cells transfer their mechanical memory to the matrix via collagen alignment and tension, and this remodeled matrix informs future cell invasion. Thus, memory-laden cells overcome mechanosensing of softer or challenging future environments via a cell-matrix transfer of memory. Consistent with model predictions, depletion of yes-associated protein destabilizes cellular memory required for collagen remodeling before invasion. We release tension in collagen fibers via laser ablation and disable fiber remodeling by lysyl-oxidase inhibition; both of which disrupt cell-to-matrix transfer of memory and hamper cross-environment invasion. These results have implications for cancer, fibrosis, and aging, where a potential cell-to-matrix transfer of mechanical memory of cells may generate prolonged cellular response. [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E22-10-0469
  27. Anal Chem. 2023 Jan 26.
    Cellular Invasion Assay for the Real-Time Tracking of Individual Cells in Spheroid or Tumor-like Mimics.
    Rachael M Kenney, Maggie C Lee, Matthew W Boyce, Zachary R Sitte, Matthew R Lockett.
      Cellular invasion is the gateway to metastasis, with cells moving from a primary tumor into neighboring regions of healthy tissue. Invasion assays provide a tractable experimental platform to quantitatively assess cellular movement in the presence of potential chemokines or inhibitors. Many such assays involve cellular movement from high cell densities to cell-free regions. To improve the physiological relevance of such assays, we developed an assay format to track cellular movement throughout a uniform density of cells. This assay format imparts diffusion-dominated environments along the channel, resulting in oxygen and nutrient gradients found in spheroids or poorly vascularized tumors. By incorporating oxygen- and pH-sensing films, we quantified spatial and temporal changes in the extracellular environment while simultaneously tracking the movement of a subset of cells engineered to express fluorescent proteins constitutively. Our results show the successful invasion into neighboring tissues likely arises from a small population with a highly invasive phenotype. These highly invasive cells continued to move throughout the 48 h experiment, suggesting they have stem-like or persister properties. Surprisingly, the distance these persister cells invaded was unaffected by the density of cells in the channel or the presence or absence of an oxygen gradient. While these datasets cannot determine if the invasive cells are inherent to the population or if diffusion-dominated environments promote them, they highlight the need for further study.
    DOI:  https://doi.org/10.1021/acs.analchem.2c05201
  28. J Cell Biol. 2023 Feb 06. pii: e202211100. [Epub ahead of print]222(2):
    Albert Reynolds (1956-2022): The father of p120.
    Gregg Wildenberg, Deborah J Mariner, Panos Z Anastasiadis, Micheal A Davis, Renee Ireton, Huapeng Yu, Andrew L Smith, Sarah Kurley, Juliet M Daniel, Agnes Roczniak-Ferguson, Xiaobo Xia, Meredith Brown, Manish Tripathi, Molly Seale, Robert Carnahan, Whitney Smalley-Freed, Michael Dohn.
      
    DOI:  https://doi.org/10.1083/jcb.202211100
  29. Front Pain Res (Lausanne). 2022 ;3 1030899
    Mechanisms of cancer pain.
    Rayan Haroun, John N Wood, Shafaq Sikandar.
      Personalised and targeted interventions have revolutionised cancer treatment and dramatically improved survival rates in recent decades. Nonetheless, effective pain management remains a problem for patients diagnosed with cancer, who continue to suffer from the painful side effects of cancer itself, as well as treatments for the disease. This problem of cancer pain will continue to grow with an ageing population and the rapid advent of more effective therapeutics to treat the disease. Current pain management guidelines from the World Health Organisation are generalised for different pain severities, but fail to address the heterogeneity of mechanisms in patients with varying cancer types, stages of disease and treatment plans. Pain is the most common complaint leading to emergency unit visits by patients with cancer and over one-third of patients that have been diagnosed with cancer will experience under-treated pain. This review summarises preclinical models of cancer pain states, with a particular focus on cancer-induced bone pain and chemotherapy-associated pain. We provide an overview of how preclinical models can recapitulate aspects of pain and sensory dysfunction that is observed in patients with persistent cancer-induced bone pain or neuropathic pain following chemotherapy. Peripheral and central nervous system mechanisms of cancer pain are discussed, along with key cellular and molecular mediators that have been highlighted in animal models of cancer pain. These include interactions between neuronal cells, cancer cells and non-neuronal cells in the tumour microenvironment. Therapeutic targets beyond opioid-based management are reviewed for the treatment of cancer pain.
    Keywords:  cancer; cancer-induced bone pain; chemotherapy associated pain; dorsal root ganglia; neuropathy; pain; sensitisation
    DOI:  https://doi.org/10.3389/fpain.2022.1030899
  30. J Cachexia Sarcopenia Muscle. 2023 Jan 25.
    Protein therapy of skeletal muscle atrophy and mechanism by angiogenic factor AGGF1.
    Zuhan He, Qixue Song, Yubing Yu, Feng Liu, Jinyan Zhao, Waikeong Un, Xingwen Da, Chengqi Xu, Yufeng Yao, Qing K Wang.
      BACKGROUND: Skeletal muscle atrophy is a common condition without a pharmacologic therapy. AGGF1 encodes an angiogenic factor that regulates cell differentiation, proliferation, migration, apoptosis, autophagy and endoplasmic reticulum stress, promotes vasculogenesis and angiogenesis and successfully treats cardiovascular diseases. Here, we report the important role of AGGF1 in the pathogenesis of skeletal muscle atrophy and attenuation of muscle atrophy by AGGF1.METHODS: In vivo studies were carried out in impaired leg muscles from patients with lumbar disc herniation, two mouse models for skeletal muscle atrophy (denervation and cancer cachexia) and heterozygous Aggf1+/- mice. Mouse muscle atrophy phenotypes were characterized by body weight and myotube cross-sectional areas (CSA) using H&E staining and immunostaining for dystrophin. Molecular mechanistic studies include co-immunoprecipitation (Co-IP), western blotting, quantitative real-time PCR analysis and immunostaining analysis.
    RESULTS: Heterozygous Aggf1+/- mice showed exacerbated phenotypes of reduced muscle mass, myotube CSA, MyHC (myosin heavy chain) and α-actin, increased inflammation (macrophage infiltration), apoptosis and fibrosis after denervation and cachexia. Intramuscular and intraperitoneal injection of recombinant AGGF1 protein attenuates atrophy phenotypes in mice with denervation (gastrocnemius weight 81.3 ± 5.7 mg vs. 67.3 ± 5.1 mg for AGGF1 vs. buffer; P < 0.05) and cachexia (133.7 ± 4.7 vs. 124.3 ± 3.2; P < 0.05). AGGF1 expression undergoes remodelling and is up-regulated in gastrocnemius and soleus muscles from atrophy mice and impaired leg muscles from patients with lumbar disc herniation by 50-60% (P < 0.01). Mechanistically, AGGF1 interacts with TWEAK (tumour necrosis factor-like weak inducer of apoptosis), which reduces interaction between TWEAK and its receptor Fn14 (fibroblast growth factor-inducing protein 14). This leads to inhibition of Fn14-induced NF-kappa B (NF-κB) p65 phosphorylation, which reduces expression of muscle-specific E3 ubiquitin ligase MuRF1 (muscle RING finger 1), resulting in increased MyHC and α-actin and partial reversal of atrophy phenotypes. Autophagy is reduced in Aggf1+/- mice due to inhibition of JNK (c-Jun N-terminal kinase) activation in denervated and cachectic muscles, and AGGF1 treatment enhances autophagy in two atrophy models by activating JNK. In impaired leg muscles of patients with lumbar disc herniation, MuRF1 is up-regulated and MyHC and α-actin are down-regulated; these effects are reversed by AGGF1 by 50% (P < 0.01).
    CONCLUSIONS: These results indicate that AGGF1 is a novel regulator for the pathogenesis of skeletal muscle atrophy and attenuates skeletal muscle atrophy by promoting autophagy and inhibiting MuRF1 expression through a molecular signalling pathway of AGGF1-TWEAK/Fn14-NF-κB. More importantly, the results indicate that AGGF1 protein therapy may be a novel approach to treat patients with skeletal muscle atrophy.
    Keywords:  AGGF1; Fn14; NF-κB; TWEAK; cancer cachexia; skeletal muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.13179
  31. Nature. 2023 Jan 25.
    Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS.
    Laura J Pallett, Leo Swadling, Mariana Diniz, Alexander A Maini, Marius Schwabenland, Adrià Dalmau Gasull, Jessica Davies, Stephanie Kucykowicz, Jessica K Skelton, Niclas Thomas, Nathalie M Schmidt, Oliver E Amin, Upkar S Gill, Kerstin A Stegmann, Alice R Burton, Emily Stephenson, Gary Reynolds, Matt Whelan, Jenifer Sanchez, Roel de Maeyer, Clare Thakker, Kornelija Suveizdyte, Imran Uddin, Ana M Ortega-Prieto, Charlotte Grant, Farid Froghi, Giuseppe Fusai, Sabela Lens, Sofia Pérez-Del-Pulgar, Walid Al-Akkad, Giuseppe Mazza, Mahdad Noursadeghi, Arne Akbar, Patrick T F Kennedy, Brian R Davidson, Marco Prinz, Benjamin M Chain, Muzlifah Haniffa, Derek W Gilroy, Marcus Dorner, Bertram Bengsch, Anna Schurich, Mala K Maini.
      The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1-4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.
    DOI:  https://doi.org/10.1038/s41586-022-05645-6
  32. JAMA Oncol. 2023 Jan 26.
    Overall Survival With Adjuvant mFOLFIRINOX for Pancreatic Cancer-Reply.
    Thierry Conroy, Florence Castan, Pascal Hammel.
      
    DOI:  https://doi.org/10.1001/jamaoncol.2022.7361
  33. JAMA Oncol. 2023 Jan 26.
    Overall Survival With Adjuvant mFOLFIRINOX for Pancreatic Cancer.
    Michele Reni, Marina Macchini, Luca Porcu.
      
    DOI:  https://doi.org/10.1001/jamaoncol.2022.7358
  34. Trends Endocrinol Metab. 2023 Jan 19. pii: S1043-2760(23)00014-0. [Epub ahead of print]
    Metabolism, homeostasis, and aging.
    Alibek Moldakozhayev, Vadim N Gladyshev.
      We propose a two-mode (pursuit/maintenance) model of metabolism defined by usable resource availability. Pursuit, consisting of anabolism and catabolism, dominates when usable resources are plentiful and leads to the generation of metabolic waste. In turn, maintenance of a system is activated by elevated metabolic waste during resource depletion. Interaction with the environment results in pendulum-like swings between these metabolic states in thriveless attempts to maintain the least deleterious organismal state - ephemeral homeostasis. Imperfectness of biological processes during these attempts supports the accumulation of the deleteriome, driving organismal aging. We discuss how metabolic adjustment by the environment and resource stabilization may modulate healthspan and lifespan.
    Keywords:  aging; homeostasis; maintenance; metabolism; pursuit
    DOI:  https://doi.org/10.1016/j.tem.2023.01.003
  35. Nat Rev Drug Discov. 2023 Jan 23.
    The KRAS crowd targets its next cancer mutations.
    Asher Mullard.
      
    DOI:  https://doi.org/10.1038/d41573-023-00015-x
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