bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023–04–16
thirty-two papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Pancreatic cancer: Advances and challenges.
  2. Metastatic dormancy needs STING.
  3. Preclinical models for drug discovery for metastatic disease.
  4. Impact of risk factors on early cancer evolution.
  5. Metastasis.
  6. Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma.
  7. An ERK1/2-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene.
  8. Insights into the metastatic cascade through research autopsies.
  9. Fibroblasts in cancer: Unity in heterogeneity.
  10. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.
  11. Genomic-transcriptomic evolution in lung cancer and metastasis.
  12. The C. elegans anchor cell transcriptome: ribosome biogenesis drives cell invasion through basement membrane.
  13. PTEN-induced kinase PINK1 supports colorectal cancer growth by regulating the labile iron pool.
  14. Body composition and lung cancer-associated cachexia in TRACERx.
  15. Lipid droplets are intracellular mechanical stressors that impair hepatocyte function.
  16. Cancer: Untangling complexity together.
  17. Ageing-associated changes in transcriptional elongation influence longevity.
  18. The relationship between epigenetic age and the hallmarks of aging in human cells.
  19. Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse.
  20. Oxygen modulates iron homeostasis by switching iron-sensing of NCOA4.
  21. Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease.
  22. RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.
  23. Development of an artificial intelligence-derived histologic signature associated with adjuvant gemcitabine treatment outcomes in pancreatic cancer.
  24. The neural addiction of cancer.
  25. Lysosomal chloride transporter CLH-6 protects lysosome membrane integrity via cathepsin activation.
  26. TBC1D15 drives regeneration of acutely damaged lysosomes.
  27. Endothelium and Subendothelial Matrix Mechanics Modulate Cancer Cell Transendothelial Migration.
  28. Epigenetic escape of immunosurveillance by malignant cell precursors.
  29. Defective import of mitochondrial metabolic enzyme elicits ectopic metabolic stress.
  30. Cancer neuroscience: State of the field, emerging directions.
  31. Oncogenic super-enhancers in cancer: mechanisms and therapeutic targets.
  32. Detection of Ras nanoclustering-dependent homo-FRET using fluorescence anisotropy measurements.
  1. Cell. 2023 Apr 13. pii: S0092-8674(23)00142-3. [Epub ahead of print]186(8): 1729-1754
    Pancreatic cancer: Advances and challenges.
    Christopher J Halbrook, Costas A Lyssiotis, Marina Pasca di Magliano, Anirban Maitra.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant disease.
    DOI:  https://doi.org/10.1016/j.cell.2023.02.014
  2. Sci Signal. 2023 Apr 11. 16(780): eadi1372
    Metastatic dormancy needs STING.
    Amy E Baek.
      STING activity in cancer cells prevents the progression of dormant metastasis.
    DOI:  https://doi.org/10.1126/scisignal.adi1372
  3. Cell. 2023 Apr 13. pii: S0092-8674(23)00169-1. [Epub ahead of print]186(8): 1792-1813
    Preclinical models for drug discovery for metastatic disease.
    Lalage Wakefield, Seema Agarwal, Kandice Tanner.
      Despite many advances, metastatic disease remains essentially uncurable. Thus, there is an urgent need to better understand mechanisms that promote metastasis, drive tumor evolution, and underlie innate and acquired drug resistance. Sophisticated preclinical models that recapitulate the complex tumor ecosystem are key to this process. We begin with syngeneic and patient-derived mouse models that are the backbone of most preclinical studies. Second, we present some unique advantages of fish and fly models. Third, we consider the strengths of 3D culture models for resolving remaining knowledge gaps. Finally, we provide vignettes on multiplexed technologies to advance our understanding of metastatic disease.
    DOI:  https://doi.org/10.1016/j.cell.2023.02.026
  4. Cell. 2023 Apr 13. pii: S0092-8674(23)00274-X. [Epub ahead of print]186(8): 1541-1563
    Impact of risk factors on early cancer evolution.
    Clare E Weeden, William Hill, Emilia L Lim, Eva Grönroos, Charles Swanton.
      Recent identification of oncogenic cells within healthy tissues and the prevalence of indolent cancers found incidentally at autopsies reveal a greater complexity in tumor initiation than previously appreciated. The human body contains roughly 40 trillion cells of 200 different types that are organized within a complex three-dimensional matrix, necessitating exquisite mechanisms to restrain aberrant outgrowth of malignant cells that have the capacity to kill the host. Understanding how this defense is overcome to trigger tumorigenesis and why cancer is so extraordinarily rare at the cellular level is vital to future prevention therapies. In this review, we discuss how early initiated cells are protected from further tumorigenesis and the non-mutagenic pathways by which cancer risk factors promote tumor growth. By nature, the absence of permanent genomic alterations potentially renders these tumor-promoting mechanisms clinically targetable. Finally, we consider existing strategies for early cancer interception with perspectives on the next steps for molecular cancer prevention.
    DOI:  https://doi.org/10.1016/j.cell.2023.03.013
  5. Cell. 2023 Apr 13. pii: S0092-8674(23)00221-0. [Epub ahead of print]186(8): 1564-1579
    Metastasis.
    Stefanie Gerstberger, Qingwen Jiang, Karuna Ganesh.
      Most cancer-associated deaths occur due to metastasis, yet our understanding of metastasis as an evolving, heterogeneous, systemic disease and of how to effectively treat it is still emerging. Metastasis requires the acquisition of a succession of traits to disseminate, variably enter and exit dormancy, and colonize distant organs. The success of these events is driven by clonal selection, the potential of metastatic cells to dynamically transition into distinct states, and their ability to co-opt the immune environment. Here, we review the main principles of metastasis and highlight emerging opportunities to develop more effective therapies for metastatic cancer.
    DOI:  https://doi.org/10.1016/j.cell.2023.03.003
  6. Cancer Cell. 2023 Apr 08. pii: S1535-6108(23)00088-0. [Epub ahead of print]
    Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma.
    Giorgio Gaglia, Megan L Burger, Cecily C Ritch, Danae Rammos, Yang Dai, Grace E Crossland, Sara Z Tavana, Simon Warchol, Alex M Jaeger, Santiago Naranjo, Shannon Coy, Ajit J Nirmal, Robert Krueger, Jia-Ren Lin, Hanspeter Pfister, Peter K Sorger, Tyler Jacks, Sandro Santagata.
      Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response. Lymphonets nucleated from small T cell clusters and incorporated B cells with increasing size. CXCR3-mediated trafficking modulated lymphonet size and number, but T cell antigen expression directed intratumoral localization. Lymphonets preferentially harbored TCF1+ PD-1+ progenitor CD8+ T cells involved in responses to immune checkpoint blockade (ICB) therapy. Upon treatment of mice with ICB or an antigen-targeted vaccine, lymphonets retained progenitor and gained cytotoxic CD8+ T cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8+ T cell anti-tumor responses.
    Keywords:  CyCIF; cancer vaccines; computational biology; immunotherapy; lung adenocarcinoma; multimodal data integration; multiplexed imaging; spatial biology; spatial profiling; systems biology
    DOI:  https://doi.org/10.1016/j.ccell.2023.03.015
  7. EMBO J. 2023 Apr 11. e110902
    An ERK1/2-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene.
    Muhammad S Azman, Emilie L Alard, Martin Dodel, Federica Capraro, Rupert Faraway, Maria Dermit, Wanling Fan, Alina Chakraborty, Jernej Ule, Faraz K Mardakheh.
      Oncogenic RAS signaling reprograms gene expression through both transcriptional and post-transcriptional mechanisms. While transcriptional regulation downstream of RAS is relatively well characterized, how RAS post-transcriptionally modulates gene expression to promote malignancy remains largely unclear. Using quantitative RNA interactome capture analysis, we here reveal that oncogenic RAS signaling reshapes the RNA-bound proteomic landscape of pancreatic cancer cells, with a network of nuclear proteins centered around nucleolin displaying enhanced RNA-binding activity. We show that nucleolin is phosphorylated downstream of RAS, which increases its binding to pre-ribosomal RNA (rRNA), boosts rRNA production, and promotes ribosome biogenesis. This nucleolin-dependent enhancement of ribosome biogenesis is crucial for RAS-induced pancreatic cancer cell proliferation and can be targeted therapeutically to inhibit tumor growth. Our results reveal that oncogenic RAS signaling drives ribosome biogenesis by regulating the RNA-binding activity of nucleolin and highlight a crucial role for this mechanism in RAS-mediated tumorigenesis.
    Keywords:  Nucleolin; RAS; RNA-binding proteins; pancreatic ductal adenocarcinoma; ribosome biogenesis
    DOI:  https://doi.org/10.15252/embj.2022110902
  8. Trends Cancer. 2023 Apr 12. pii: S2405-8033(23)00031-6. [Epub ahead of print]
    Insights into the metastatic cascade through research autopsies.
    Sonya Hessey, Petros Fessas, Simone Zaccaria, Mariam Jamal-Hanjani, Charles Swanton.
      Metastasis is a complex process and the leading cause of cancer-related death globally. Recent studies have demonstrated that genomic sequencing data from paired primary and metastatic tumours can be used to trace the evolutionary origins of cells responsible for metastasis. This approach has yielded new insights into the genomic alterations that engender metastatic potential, and the mechanisms by which cancer spreads. Given that the reliability of these approaches is contingent upon how representative the samples are of primary and metastatic tumour heterogeneity, we review insights from studies that have reconstructed the evolution of metastasis within the context of their cohorts and designs. We discuss the role of research autopsies in achieving the comprehensive sampling necessary to advance the current understanding of metastasis.
    Keywords:  genomic sequencing; metastasis; research autopsy; tumour evolution
    DOI:  https://doi.org/10.1016/j.trecan.2023.03.002
  9. Cell. 2023 Apr 13. pii: S0092-8674(23)00277-5. [Epub ahead of print]186(8): 1580-1609
    Fibroblasts in cancer: Unity in heterogeneity.
    Yash Chhabra, Ashani T Weeraratna.
      Tumor cells do not exist in isolation in vivo, and carcinogenesis depends on the surrounding tumor microenvironment (TME), composed of a myriad of cell types and biophysical and biochemical components. Fibroblasts are integral in maintaining tissue homeostasis. However, even before a tumor develops, pro-tumorigenic fibroblasts in close proximity can provide the fertile 'soil' to the cancer 'seed' and are known as cancer-associated fibroblasts (CAFs). In response to intrinsic and extrinsic stressors, CAFs reorganize the TME enabling metastasis, therapeutic resistance, dormancy and reactivation by secreting cellular and acellular factors. In this review, we summarize the recent discoveries on CAF-mediated cancer progression with a particular focus on fibroblast heterogeneity and plasticity.
    DOI:  https://doi.org/10.1016/j.cell.2023.03.016
  10. Nat Med. 2023 Apr 12.
    Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.
    TRACERx Consortium
      Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk.
    DOI:  https://doi.org/10.1038/s41591-023-02230-w
  11. Nature. 2023 Apr 12.
    Genomic-transcriptomic evolution in lung cancer and metastasis.
    TRACERx Consortium
      Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic-transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary-metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.
    DOI:  https://doi.org/10.1038/s41586-023-05706-4
  12. Development. 2023 Apr 11. pii: dev.201570. [Epub ahead of print]
    The C. elegans anchor cell transcriptome: ribosome biogenesis drives cell invasion through basement membrane.
    Daniel S Costa, Isabel W Kenny-Ganzert, Qiuyi Chi, Kieop Park, Laura C Kelley, Aastha Garde, David Q Matus, Junhyun Park, Shaul Yogev, Bob Goldstein, Theresa V Gibney, Ariel M Pani, David R Sherwood.
      Cell invasion through basement membrane (BM) barriers is important in development, immune function, and cancer progression. As invasion through BM is often stochastic, capturing gene expression profiles of actively invading cells in vivo remains elusive. Using the stereotyped timing of C. elegans anchor cell (AC) invasion, we generated an AC transcriptome during BM breaching. Through a focused RNAi screen of transcriptionally enriched genes, we identified new invasion regulators, including TCTP (translationally controlled tumor protein). We also discovered gene enrichment of ribosomal proteins. AC-specific RNAi, endogenous ribosome labeling, and ribosome biogenesis analysis revealed a burst of ribosome production occurs shortly after AC specification, which drives the translation of proteins mediating BM removal. Ribosomes also enrich near the AC endoplasmic reticulum (ER) Sec61 translocon and the endomembrane system expands prior to invasion. We show that AC invasion is sensitive to ER stress, indicating a heightened requirement for translation of ER trafficked proteins. These studies reveal key roles for ribosome biogenesis and endomembrane expansion in cell invasion through BM and establish the AC transcriptome as a resource to identify mechanisms underlying BM transmigration.
    Keywords:  Basement membrane; Cell invasion; Endomembrane expansion; Ribosome biogenesis; Transcriptome; Translationally controlled tumor protein (TCTP)
    DOI:  https://doi.org/10.1242/dev.201570
  13. J Biol Chem. 2023 Apr 08. pii: S0021-9258(23)00333-2. [Epub ahead of print] 104691
    PTEN-induced kinase PINK1 supports colorectal cancer growth by regulating the labile iron pool.
    Brandon Chen, Nupur K Das, Indrani Talukder, Rashi Singhal, Cristina Castillo, Anthony Andren, Joseph D Mancias, Costas A Lyssiotis, Yatrik M Shah.
      Mitophagy is a cargo-specific autophagic process that recycles damaged mitochondria to promote mitochondrial turnover. PTEN-induced putative kinase 1 (PINK1) mediates the canonical mitophagic pathway. However, the role of PINK1 in diseases where mitophagy has been purported to play a role, such as colorectal cancer, in unclear.Our results here demonstrate that higher PINK1 expression is positively correlated with decreased colon cancer survival, and mitophagy is required for colon cancer growth following nutrient stress. We show that doxycycline-inducible knockdown (KD) of PINK1 in a panel of colon cancer cell lines inhibited proliferation, whereas disruption of other mitophagy receptors did not impact cell growth. We observed that PINK KD led to a decrease in mitochondrial respiration, membrane hyperpolarization, accumulation of mitochondrial DNA, and depletion of antioxidant glutathione. In addition, mitochondria are important hubs for the utilization of iron and synthesizing iron-dependent cofactors such as heme and iron sulfur clusters. We observed an increase in the iron storage protein ferritin and a decrease labile iron pool in the PINK1 KD cells, but total cellular iron or markers of iron starvation/overload were not affected. Finally, cellular iron storage and the labile iron pool are maintained via autophagic degradation of ferritin (ferritinophagy). We found overexpressing nuclear receptor coactivator 4, a key adaptor for ferritinophagy, rescued cell growth and the labile iron pool in PINK1 KD cells. These results indicate that PINK1 integrates mitophagy and ferritinophagy to regulate intracellular iron availability and is essential for maintaining intracellular iron homeostasis to support survival and growth in colorectal cancer cells.
    Keywords:  colon cancer; ferritinophagy; iron; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.jbc.2023.104691
  14. Nat Med. 2023 Apr 12.
    Body composition and lung cancer-associated cachexia in TRACERx.
    TRACERx Consortium
      Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.
    DOI:  https://doi.org/10.1038/s41591-023-02232-8
  15. Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2216811120
    Lipid droplets are intracellular mechanical stressors that impair hepatocyte function.
    Abigail E Loneker, Farid Alisafaei, Aayush Kant, David Li, Paul A Janmey, Vivek B Shenoy, Rebecca G Wells.
      Matrix stiffening and external mechanical stress have been linked to disease and cancer development in multiple tissues, including the liver, where cirrhosis (which increases stiffness markedly) is the major risk factor for hepatocellular carcinoma. Patients with nonalcoholic fatty liver disease and lipid droplet-filled hepatocytes, however, can develop cancer in noncirrhotic, relatively soft tissue. Here, by treating primary human hepatocytes with the monounsaturated fatty acid oleate, we show that lipid droplets are intracellular mechanical stressors with similar effects to tissue stiffening, including nuclear deformation, chromatin condensation, and impaired hepatocyte function. Mathematical modeling of lipid droplets as inclusions that have only mechanical interactions with other cellular components generated results consistent with our experiments. These data show that lipid droplets are intracellular sources of mechanical stress and suggest that nuclear membrane tension integrates cell responses to combined internal and external stresses.
    Keywords:  HNF4α; chromatin condensation; cytoskeleton; mechanobiology; nuclear deformation
    DOI:  https://doi.org/10.1073/pnas.2216811120
  16. Cell. 2023 Apr 13. pii: S0092-8674(23)00284-2. [Epub ahead of print]186(8): 1513-1514
    Cancer: Untangling complexity together.
    Cell editorial team
      
    DOI:  https://doi.org/10.1016/j.cell.2023.03.021
  17. Nature. 2023 Apr 12.
    Ageing-associated changes in transcriptional elongation influence longevity.
    Cédric Debès, Antonios Papadakis, Sebastian Grönke, Özlem Karalay, Luke S Tain, Athanasia Mizi, Shuhei Nakamura, Oliver Hahn, Carina Weigelt, Natasa Josipovic, Anne Zirkel, Isabell Brusius, Konstantinos Sofiadis, Mantha Lamprousi, Yu-Xuan Lu, Wenming Huang, Reza Esmaillie, Torsten Kubacki, Martin R Späth, Bernhard Schermer, Thomas Benzing, Roman-Ulrich Müller, Adam Antebi, Linda Partridge, Argyris Papantonis, Andreas Beyer.
      Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1-4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.
    DOI:  https://doi.org/10.1038/s41586-023-05922-y
  18. Nat Aging. 2022 Jun;2(6): 484-493
    The relationship between epigenetic age and the hallmarks of aging in human cells.
    Sylwia Kabacik, Donna Lowe, Leonie Fransen, Martin Leonard, Siew-Lan Ang, Christopher Whiteman, Sarah Corsi, Howard Cohen, Sarah Felton, Radhika Bali, Steve Horvath, Ken Raj.
      Epigenetic clocks are mathematically derived age estimators that are based on combinations of methylation values that change with age at specific CpGs in the genome. These clocks are widely used to measure the age of tissues and cells1,2. The discrepancy between epigenetic age (EpiAge), as estimated by these clocks, and chronological age is referred to as EpiAge acceleration. Epidemiological studies have linked EpiAge acceleration to a wide variety of pathologies, health states, lifestyle, mental state and environmental factors2, indicating that epigenetic clocks tap into critical biological processes that are involved in aging. Despite the importance of this inference, the mechanisms underpinning these clocks remained largely uncharacterized and unelucidated. Here, using primary human cells, we set out to investigate whether epigenetic aging is the manifestation of one or more of the aging hallmarks previously identified3. We show that although epigenetic aging is distinct from cellular senescence, telomere attrition and genomic instability, it is associated with nutrient sensing, mitochondrial activity and stem cell composition.
    DOI:  https://doi.org/10.1038/s43587-022-00220-0
  19. Chem Sci. 2023 Apr 05. 14(14): 3881-3892
    Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse.
    Jasmine Wyatt, Yuen Ka Chan, Mateusz Hess, Mahvash Tavassoli, Manuel M Müller.
      Apoptin is a small viral protein capable of inducing cell death selectively in cancer cells. Despite its potential as an anticancer agent, relatively little is known about its mechanism of toxicity and cancer-selectivity. Previous experiments suggest that cancer-selective phosphorylation modulates apoptin toxicity, although a lack of chemical tools has hampered the dissection of underlying mechanisms. Here, we describe structure-function studies with site-specifically phosphorylated apoptin (apoptin-T108ph) in living cells which revealed that Thr108 phosphorylation is the selectivity switch for apoptin toxicity. Mechanistic investigations link T108ph to actin binding, cytoskeletal disruption and downstream inhibition of anoikis-resistance as well as cancer cell invasion. These results establish apoptin as a protein pro-drug, selectively activated in cancer cells by phosphorylation, which disrupts the cytoskeleton and promotes cell death. We anticipate that this mechanism provides a framework for the design of next generation anticancer proteins with enhanced selectivity and potency.
    DOI:  https://doi.org/10.1039/d2sc04481a
  20. J Biol Chem. 2023 Apr 12. pii: S0021-9258(23)00343-5. [Epub ahead of print] 104701
    Oxygen modulates iron homeostasis by switching iron-sensing of NCOA4.
    Sota Kuno, Kazuhiro Iwai.
      To ensure proper utilization of iron and avoid its toxicity, cells are equipped with iron-sensing proteins to maintain cellular iron homeostasis. We showed previously that NCOA4, a ferritin-specific autophagy adapter, intricately regulates the fate of ferritin; upon binding to Fe3+, NCOA4 forms insoluble condensates and regulates ferritin autophagy in iron-replete conditions. Here, we demonstrate an additional iron-sensing mechanism of NCOA4. Our results indicate that the insertion of an Fe-S cluster enables preferential recognition of NCOA4 by the HERC2 ubiquitin ligase in iron-replete conditions, resulting in degradation by the proteasome and subsequent inhibition of ferritinophagy. We also found that both condensation and ubiquitin-mediated degradation of NCOA4 can occur in the same cell, and the cellular oxygen tension determines the selection of these pathways. Fe-S cluster-mediated degradation of NCOA4 is enhanced under hypoxia, whereas NCOA4 forms condensates and degrades ferritin at higher oxygen levels. Considering the involvement of iron in oxygen handling, our findings demonstrate that the NCOA4/ferritin axis is another layer of cellular iron regulation in response to oxygen levels.
    Keywords:  autophagy; ferritin; hypoxia; iron metabolism; iron-sulfur protein
    DOI:  https://doi.org/10.1016/j.jbc.2023.104701
  21. Cell. 2023 Apr 05. pii: S0092-8674(23)00275-1. [Epub ahead of print]
    Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease.
    Zixi Wang, Shijia Zhu, Yuemeng Jia, Yunguan Wang, Naoto Kubota, Naoto Fujiwara, Ruth Gordillo, Cheryl Lewis, Min Zhu, Tripti Sharma, Lin Li, Qiyu Zeng, Yu-Hsuan Lin, Meng-Hsiung Hsieh, Purva Gopal, Tao Wang, Matt Hoare, Peter Campbell, Yujin Hoshida, Hao Zhu.
      Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Tbx3, Bcl6, or Smyd2 resulted in protection against hepatic steatosis. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease.
    Keywords:  Gpam; Mboat7; NAFLD; NASH; Smyd2; Tbx3; chronic liver disease; fatty liver disease; in vivo screening; somatic mosaicism
    DOI:  https://doi.org/10.1016/j.cell.2023.03.014
  22. Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2220340120
    RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.
    Francesco Scavone, Samantha C Gumbin, Paul A Da Rosa, Ron R Kopito.
      Ribosomes that stall while translating cytosolic proteins are incapacitated by incomplete nascent chains, termed "arrest peptides" (APs) that are destroyed by the ubiquitin proteasome system (UPS) via a process known as the ribosome-associated quality control (RQC) pathway. By contrast, APs on ribosomes that stall while translocating secretory proteins into the endoplasmic reticulum (ER-APs) are shielded from cytosol by the ER membrane and the tightly sealed ribosome-translocon junction (RTJ). How this junction is breached to enable access of cytosolic UPS machinery and 26S proteasomes to translocon- and ribosome-obstructing ER-APs is not known. Here, we show that UPS and RQC-dependent degradation of ER-APs strictly requires conjugation of the ubiquitin-like (Ubl) protein UFM1 to 60S ribosomal subunits at the RTJ. Therefore, UFMylation of translocon-bound 60S subunits modulates the RTJ to promote access of proteasomes and RQC machinery to ER-APs.
    Keywords:  UFM1; UFMylation; endoplasmic reticulum; ribosome-associated quality control; ubiquitin
    DOI:  https://doi.org/10.1073/pnas.2220340120
  23. Cell Rep Med. 2023 Apr 05. pii: S2666-3791(23)00123-4. [Epub ahead of print] 101013
    Development of an artificial intelligence-derived histologic signature associated with adjuvant gemcitabine treatment outcomes in pancreatic cancer.
    Vivek Nimgaonkar, Viswesh Krishna, Vrishab Krishna, Ekin Tiu, Anirudh Joshi, Damir Vrabac, Hriday Bhambhvani, Katelyn Smith, Julia S Johansen, Shalini Makawita, Benjamin Musher, Arnav Mehta, Andrew Hendifar, Zev Wainberg, Davendra Sohal, Christos Fountzilas, Aatur Singhi, Pranav Rajpurkar, Eric A Collisson.
      Pancreatic ductal adenocarcinoma (PDAC) has been left behind in the evolution of personalized medicine. Predictive markers of response to therapy are lacking in PDAC despite various histological and transcriptional classification schemes. We report an artificial intelligence (AI) approach to histologic feature examination that extracts a signature predictive of disease-specific survival (DSS) in patients with PDAC receiving adjuvant gemcitabine. We demonstrate that this AI-generated histologic signature is associated with outcomes following adjuvant gemcitabine, while three previously developed transcriptomic classification systems are not (n = 47). We externally validate this signature in an independent cohort of patients treated with adjuvant gemcitabine (n = 46). Finally, we demonstrate that the signature does not stratify survival outcomes in a third cohort of untreated patients (n = 161), suggesting that the signature is specifically predictive of treatment-related outcomes but is not generally prognostic. This imaging analysis pipeline has promise in the development of actionable markers in other clinical settings where few biomarkers currently exist.
    Keywords:  digital pathology; pancreatic cancer; predictive biomarker
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101013
  24. Nat Rev Cancer. 2023 Apr 11.
    The neural addiction of cancer.
    Claire Magnon, Hubert Hondermarck.
      The recently uncovered key role of the peripheral and central nervous systems in controlling tumorigenesis and metastasis has opened a new area of research to identify innovative approaches against cancer. Although the 'neural addiction' of cancer is only partially understood, in this Perspective we discuss the current knowledge and perspectives on peripheral and central nerve circuitries and brain areas that can support tumorigenesis and metastasis and the possible reciprocal influence that the brain and peripheral tumours exert on one another. Tumours can build up local autonomic and sensory nerve networks and are able to develop a long-distance relationship with the brain through circulating adipokines, inflammatory cytokines, neurotrophic factors or afferent nerve inputs, to promote cancer initiation, growth and dissemination. In turn, the central nervous system can affect tumour development and metastasis through the activation or dysregulation of specific central neural areas or circuits, as well as neuroendocrine, neuroimmune or neurovascular systems. Studying neural circuitries in the brain and tumours, as well as understanding how the brain communicates with the tumour or how intratumour nerves interplay with the tumour microenvironment, can reveal unrecognized mechanisms that promote cancer development and progression and open up opportunities for the development of novel therapeutic strategies. Targeting the dysregulated peripheral and central nervous systems might represent a novel strategy for next-generation cancer treatment that could, in part, be achieved through the repurposing of neuropsychiatric drugs in oncology.
    DOI:  https://doi.org/10.1038/s41568-023-00556-8
  25. J Cell Biol. 2023 Jun 05. pii: e202210063. [Epub ahead of print]222(6):
    Lysosomal chloride transporter CLH-6 protects lysosome membrane integrity via cathepsin activation.
    Qianqian Zhang, Yuan Li, Youli Jian, Meijiao Li, Xiaochen Wang.
      Lysosomal integrity is vital for cell homeostasis, but the underlying mechanisms are poorly understood. Here, we identify CLH-6, the C. elegans ortholog of the lysosomal Cl-/H+ antiporter ClC-7, as an important factor for protecting lysosomal integrity. Loss of CLH-6 affects lysosomal degradation, causing cargo accumulation and membrane rupture. Reducing cargo delivery or increasing CPL-1/cathepsin L or CPR-2/cathepsin B expression suppresses these lysosomal defects. Inactivation of CPL-1 or CPR-2, like CLH-6 inactivation, affects cargo digestion and causes lysosomal membrane rupture. Thus, loss of CLH-6 impairs cargo degradation, leading to membrane damage of lysosomes. In clh-6(lf) mutants, lysosomes are acidified as in wild type but contain lower chloride levels, and cathepsin B and L activities are significantly reduced. Cl- binds to CPL-1 and CPR-2 in vitro, and Cl- supplementation increases lysosomal cathepsin B and L activities. Altogether, these findings suggest that CLH-6 maintains the luminal chloride levels required for cathepsin activity, thus facilitating substrate digestion to protect lysosomal membrane integrity.
    DOI:  https://doi.org/10.1083/jcb.202210063
  26. Nat Cell Biol. 2023 Apr 12.
    TBC1D15 drives regeneration of acutely damaged lysosomes.
      
    DOI:  https://doi.org/10.1038/s41556-023-01135-7
  27. Adv Sci (Weinh). 2023 Apr 13. e2206554
    Endothelium and Subendothelial Matrix Mechanics Modulate Cancer Cell Transendothelial Migration.
    Yousef Javanmardi, Ayushi Agrawal, Andrea Malandrino, Soufian Lasli, Michelle Chen, Somayeh Shahreza, Bianca Serwinski, Leila Cammoun, Ran Li, Mehdi Jorfi, Boris Djordjevic, Nicolas Szita, Fabian Spill, Sergio Bertazzo, Graham K Sheridan, Vivek Shenoy, Fernando Calvo, Roger Kamm, Emad Moeendarbary.
      Cancer cell extravasation, a key step in the metastatic cascade, involves cancer cell arrest on the endothelium, transendothelial migration (TEM), followed by the invasion into the subendothelial extracellular matrix (ECM) of distant tissues. While cancer research has mostly focused on the biomechanical interactions between tumor cells (TCs) and ECM, particularly at the primary tumor site, very little is known about the mechanical properties of endothelial cells and the subendothelial ECM and how they contribute to the extravasation process. Here, an integrated experimental and theoretical framework is developed to investigate the mechanical crosstalk between TCs, endothelium and subendothelial ECM during in vitro cancer cell extravasation. It is found that cancer cell actin-rich protrusions generate complex push-pull forces to initiate and drive TEM, while transmigration success also relies on the forces generated by the endothelium. Consequently, mechanical properties of the subendothelial ECM and endothelial actomyosin contractility that mediate the endothelial forces also impact the endothelium's resistance to cancer cell transmigration. These results indicate that mechanical features of distant tissues, including force interactions between the endothelium and the subendothelial ECM, are key determinants of metastatic organotropism.
    Keywords:  biomaterial properties; cancer cell extravasation; computational modeling; metastasis; traction force microscopy
    DOI:  https://doi.org/10.1002/advs.202206554
  28. EMBO J. 2023 Apr 13. e114050
    Epigenetic escape of immunosurveillance by malignant cell precursors.
    Claudia Galassi, Lorenzo Galluzzi.
      Newly formed malignant cells must escape immunosurveillance to generate progressing neoplastic lesions of clinical relevance. Recent data indicate that the immunogenicity of nascent cancer cells, at least in some settings, is dictated by inherent epigenetic mechanisms rather than by immunoediting and the consequent Darwinian selection of poorly immunogenic phenotypes.
    Keywords:  CSDE1; SMYD3; STAT1; cancer stem cells; immunotherapy; intratumoral heterogeneity
    DOI:  https://doi.org/10.15252/embj.2023114050
  29. Sci Adv. 2023 Apr 14. 9(15): eadf1956
    Defective import of mitochondrial metabolic enzyme elicits ectopic metabolic stress.
    Kazuya Nishio, Tomoyuki Kawarasaki, Yuki Sugiura, Shunsuke Matsumoto, Ayano Konoshima, Yuki Takano, Mayuko Hayashi, Fumihiko Okumura, Takumi Kamura, Tsunehiro Mizushima, Kunio Nakatsukasa.
      Deficiencies in mitochondrial protein import are associated with a number of diseases. However, although nonimported mitochondrial proteins are at great risk of aggregation, it remains largely unclear how their accumulation causes cell dysfunction. Here, we show that nonimported citrate synthase is targeted for proteasomal degradation by the ubiquitin ligase SCFUcc1. Unexpectedly, our structural and genetic analyses revealed that nonimported citrate synthase appears to form an enzymatically active conformation in the cytosol. Its excess accumulation caused ectopic citrate synthesis, which, in turn, led to an imbalance in carbon flux of sugar, a reduction of the pool of amino acids and nucleotides, and a growth defect. Under these conditions, translation repression is induced and acts as a protective mechanism that mitigates the growth defect. We propose that the consequence of mitochondrial import failure is not limited to proteotoxic insults, but that the accumulation of a nonimported metabolic enzyme elicits ectopic metabolic stress.
    DOI:  https://doi.org/10.1126/sciadv.adf1956
  30. Cell. 2023 Apr 13. pii: S0092-8674(23)00104-6. [Epub ahead of print]186(8): 1689-1707
    Cancer neuroscience: State of the field, emerging directions.
    Frank Winkler, Humsa S Venkatesh, Moran Amit, Tracy Batchelor, Ihsan Ekin Demir, Benjamin Deneen, David H Gutmann, Shawn Hervey-Jumper, Thomas Kuner, Donald Mabbott, Michael Platten, Asya Rolls, Erica K Sloan, Timothy C Wang, Wolfgang Wick, Varun Venkataramani, Michelle Monje.
      The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new pillar of cancer therapy.
    DOI:  https://doi.org/10.1016/j.cell.2023.02.002
  31. Cancer Metastasis Rev. 2023 Apr 14.
    Oncogenic super-enhancers in cancer: mechanisms and therapeutic targets.
    Megan Bacabac, Wei Xu.
      Activation of oncogenes to sustain proliferative signaling and initiate metastasis are important hallmarks of cancer. Oncogenes are amplified or overexpressed in cancer cells and overexpression is often controlled at the level of transcription. Gene expression is tightly controlled by many cis-regulatory elements and trans-acting factors. Large clusters of enhancers known as "super-enhancers" drive robust expression of cell-fate determining transcription factors in cell identity. Cancer cells can take advantage of super-enhancers and become transcriptionally addicted to them leading to tumorigenesis and metastasis. Additionally, the cis-regulatory landscape of cancer includes aberrant super-enhancers that are not present in normal cells. The landscape of super-enhancers in cancer is characterized by high levels of histone H3K27 acetylation and bromodomain-containing protein 4 (BRD4), and Mediator complex. These chromatin features facilitate the identification of cancer type-specific and cell-type-specific super-enhancers that control the expression of important oncogenes to stimulate their growth. Disruption of super-enhancers via inhibiting BRD4 or other epigenetic proteins is a potential therapeutic option. Here, we will describe the discovery of super-enhancers and their unique characteristics compared to typical enhancers. Then, we will highlight how super-enhancer-associated genes contribute to cancer progression in different solid tumor types. Lastly, we will cover therapeutic targets and their epigenetic modulators.
    Keywords:  BRD4; Enhancer reprogramming; Epigenetic modulators; Mediator; Metastasis; Super-enhancers
    DOI:  https://doi.org/10.1007/s10555-023-10103-4
  32. Eur J Cell Biol. 2023 Apr 11. pii: S0171-9335(23)00029-8. [Epub ahead of print]102(2): 151314
    Detection of Ras nanoclustering-dependent homo-FRET using fluorescence anisotropy measurements.
    Ganesh Babu Manoharan, Camilo Guzmán, Arafath Kaja Najumudeen, Daniel Abankwa.
      The small GTPase Ras is frequently mutated in cancer and a driver of tumorigenesis. The recent years have shown great progress in drug-targeting Ras and understanding how it operates on the plasma membrane. We now know that Ras is non-randomly organized into proteo-lipid complexes on the membrane, called nanoclusters. Nanoclusters contain only a few Ras proteins and are necessary for the recruitment of downstream effectors, such as Raf. If tagged with fluorescent proteins, the dense packing of Ras in nanoclusters can be analyzed by Förster/ fluorescence resonance energy transfer (FRET). Loss of FRET can therefore report on decreased nanoclustering and any process upstream of it, such as Ras lipid modifications and correct trafficking. Thus, cellular FRET screens employing Ras-derived fluorescence biosensors are potentially powerful tools to discover chemical or genetic modulators of functional Ras membrane organization. Here we implement fluorescence anisotropy-based homo-FRET measurements of Ras-derived constructs labelled with only one fluorescent protein on a confocal microscope and a fluorescence plate reader. We show that homo-FRET of both H-Ras- and K-Ras-derived constructs can sensitively report on Ras-lipidation and -trafficking inhibitors, as well as on genetic perturbations of proteins regulating membrane anchorage. By exploiting the switch I/II-binding Ras-dimerizing compound BI-2852, this assay is also suitable to report on the engagement of the K-Ras switch II pocket by small molecules such as AMG 510. Given that homo-FRET only requires one fluorescent protein tagged Ras construct, this approach has significant advantages to create Ras-nanoclustering FRET-biosensor reporter cell lines, as compared to the more common hetero-FRET approaches.
    Keywords:  Anisotropy; Drug discovery; Homo-FRET; Nanoclustering; Ras
    DOI:  https://doi.org/10.1016/j.ejcb.2023.151314
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