bims-proteo Biomed News
on Proteostasis
Issue of 2022–11–27
fourteen papers selected by
Eric Chevet, INSERM
  1. Dynamic quality control machinery that operates across compartmental borders mediates the degradation of mammalian nuclear membrane proteins.
  2. Identification of ester-linked ubiquitylation sites during TLR7 signalling increases the number of inter-ubiquitin linkages from eight to twelve.
  3. Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair.
  4. Quantitative proteome dataset profiling of UBC4 and UBC5 deletion strains in Saccharomyces cerevisiae.
  5. Calreticulin mutations affect its chaperone function and perturb the glycoproteome.
  6. FACS-mediated isolation of native autophagic vesicles.
  7. Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.
  8. A deubiquitination module essential for Treg fitness in the tumor microenvironment.
  9. Enhanced access to the human phosphoproteome with genetically encoded phosphothreonine.
  10. Resistance Training Modulates Reticulum Endoplasmic Stress, Independent of Oxidative and Inflammatory Responses, in Elderly People.
  11. Autophagic lysosome reformation in health and disease.
  12. Autophagy promotes cell survival by maintaining NAD levels.
  13. Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.
  14. Spatial intra-tumor heterogeneity is associated with survival of lung adenocarcinoma patients.
  1. Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01549-2. [Epub ahead of print]41(8): 111675
    Dynamic quality control machinery that operates across compartmental borders mediates the degradation of mammalian nuclear membrane proteins.
    Pei-Ling Tsai, Christopher J F Cameron, Maria Fernanda Forni, Renee R Wasko, Brigitte S Naughton, Valerie Horsley, Mark B Gerstein, Christian Schlieker.
      Many human diseases are caused by mutations in nuclear envelope (NE) proteins. How protein homeostasis and disease etiology are interconnected at the NE is poorly understood. Specifically, the identity of local ubiquitin ligases that facilitate ubiquitin-proteasome-dependent NE protein turnover is presently unknown. Here, we employ a short-lived, Lamin B receptor disease variant as a model substrate in a genetic screen to uncover key elements of NE protein turnover. We identify the ubiquitin-conjugating enzymes (E2s) Ube2G2 and Ube2D3, the membrane-resident ubiquitin ligases (E3s) RNF5 and HRD1, and the poorly understood protein TMEM33. RNF5, but not HRD1, requires TMEM33 both for efficient biosynthesis and function. Once synthesized, RNF5 responds dynamically to increased substrate levels at the NE by departing from the endoplasmic reticulum, where HRD1 remains confined. Thus, mammalian protein quality control machinery partitions between distinct cellular compartments to address locally changing substrate loads, establishing a robust cellular quality control system.
    Keywords:  CP: Molecular biology; CRISPR screen; ERAD; RNF5; TMEM33; nuclear envelopathies; proteasome; protein quality control; protein turnover; proteostasis; ubiquitin ligase
    DOI:  https://doi.org/10.1016/j.celrep.2022.111675
  2. Biochem J. 2022 Nov 21. pii: BCJ20220510. [Epub ahead of print]
    Identification of ester-linked ubiquitylation sites during TLR7 signalling increases the number of inter-ubiquitin linkages from eight to twelve.
    Elisha Honami McCrory, Vyacheslav Akimov, Philip Cohen, Blagoy Blagoev.
      The E3 ligase HOIL-1 forms ester bonds in vitro between ubiquitin and serine/threonine residues in proteins. Here, we exploit UbiSite technology to identify serine and threonine residues undergoing HOIL-1 catalysed ubiquitylation in macrophages stimulated with R848, an activator of the TLR7/8 heterodimer. We identify Thr12, Thr14, Ser20 and Thr22 of ubiquitin as amino acid residues forming ester bonds with the C-terminal carboxylate of another ubiquitin molecule. This increases from 8 to 12 the number of ubiquitin linkage types that are formed in cells. We also identify Ser175 of IRAK4, Ser136, Thr163 and Ser168 of IRAK2 and Thr141 of MyD88 as further sites of HOIL-1-catalysed ubiquitylation together with lysine residues in these proteins that also undergo R848-dependent ubiquitylation. These findings establish that the ubiquitin chains attached to components of myddosomes are initiated by both ester and isopeptide bonds. Ester bond formation takes place within the proline, serine, threonine-rich (PST) domains of IRAK2 and IRAK4 and the intermediate domain of MyD88. The ubiquitin molecules attached to Lys162, Thr163 and Ser168 of IRAK2 are attached to different IRAK2 molecules.
    Keywords:  HOIL-1; innate immunity; toll-like receptors; ubiquitin ligases; ubiquitins
    DOI:  https://doi.org/10.1042/BCJ20220510
  3. EMBO J. 2022 Nov 21. e112677
    Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair.
    Maja Radulovic, Eva Maria Wenzel, Sania Gilani, Lya Kk Holland, Alf Håkon Lystad, Santosh Phuyal, Vesa M Olkkonen, Andreas Brech, Marja Jäättelä, Kenji Maeda, Camilla Raiborg, Harald Stenmark.
      Lysosome integrity is essential for cell viability, and lesions in lysosome membranes are repaired by the ESCRT machinery. Here, we describe an additional mechanism for lysosome repair that is activated independently of ESCRT recruitment. Lipidomic analyses showed increases in lysosomal phosphatidylserine and cholesterol after damage. Electron microscopy demonstrated that lysosomal membrane damage is rapidly followed by the formation of contacts with the endoplasmic reticulum (ER), which depends on the ER proteins VAPA/B. The cholesterol-binding protein ORP1L was recruited to damaged lysosomes, accompanied by cholesterol accumulation by a mechanism that required VAP-ORP1L interactions. The PtdIns 4-kinase PI4K2A rapidly produced PtdIns4P on lysosomes upon damage, and knockout of PI4K2A inhibited damage-induced accumulation of ORP1L and cholesterol and led to the failure of lysosomal membrane repair. The cholesterol-PtdIns4P transporter OSBP was also recruited upon damage, and its depletion caused lysosomal accumulation of PtdIns4P and resulted in cell death. We conclude that ER contacts are activated on damaged lysosomes in parallel to ESCRTs to provide lipids for membrane repair, and that PtdIns4P generation and removal are central in this response.
    Keywords:  cholesterol; lysosome; membrane contact site; membrane repair; phosphoinositide
    DOI:  https://doi.org/10.15252/embj.2022112677
  4. Data Brief. 2022 Dec;45 108737
    Quantitative proteome dataset profiling of UBC4 and UBC5 deletion strains in Saccharomyces cerevisiae.
    Valentina Rossio, Joao A Paulo.
      The Ubiquitin-Proteasome System (UPS) regulates many cellular processes in eukaryotic cells. Ubiquitylation by the UPS mainly directs proteins to proteasomal degradation, but it can also have non-degradative functions, such as regulating protein activity or localization. The small protein ubiquitin is conjugated to its substrates via a cascade of E1-E2-E3 enzymes. Dysregulation of the UPS has been implicated in the genesis and progression of many diseases, such as neurodegenerative diseases and cancer; thus, the UPS components are attractive targets for developing pharmaceutical drugs. E2s, or ubiquitin conjugating enzymes, are central players of the UPS. E2s function in tandem with specific ubiquitin ligases (E3s) to transfer ubiquitin to substrates. Here, we present the first proteome stability analysis of two closely related ubiquitin conjugating enzymes, Ubc4 and Ubc5, in S. cerevisiae. These two E2s are nearly identical, having 92% sequence identity and differing by only 11 amino acid residues. This dataset is of broad interest because higher eukaryotes express ubiquitin conjugating enzymes that are analogous to the yeast Ubc4/5. The data have been deposited in ProteomeXchange with the dataset identifier PXD037315.
    Keywords:  Isobaric tagging; Protein stability; TMT; Ubiquitin proteasome system; Yeast
    DOI:  https://doi.org/10.1016/j.dib.2022.108737
  5. Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01563-7. [Epub ahead of print]41(8): 111689
    Calreticulin mutations affect its chaperone function and perturb the glycoproteome.
    Patrick M Schürch, Liliana Malinovska, Mohammad Hleihil, Marco Losa, Mara C Hofstetter, Mattheus H E Wildschut, Veronika Lysenko, Asvin K K Lakkaraju, Christina A Maat, Dietmar Benke, Adriano Aguzzi, Bernd Wollscheid, Paola Picotti, Alexandre P A Theocharides.
      Calreticulin (CALR) is an endoplasmic reticulum (ER)-retained chaperone that assists glycoproteins in obtaining their structure. CALR mutations occur in patients with myeloproliferative neoplasms (MPNs), and the ER retention of CALR mutants (CALR MUT) is reduced due to a lacking KDEL sequence. Here, we investigate the impact of CALR mutations on protein structure and protein levels in MPNs by subjecting primary patient samples and CALR-mutated cell lines to limited proteolysis-coupled mass spectrometry (LiP-MS). Especially glycoproteins are differentially expressed and undergo profound structural alterations in granulocytes and cell lines with homozygous, but not with heterozygous, CALR mutations. Furthermore, homozygous CALR mutations and loss of CALR equally perturb glycoprotein integrity, suggesting that loss-of-function attributes of mutated CALR chaperones (CALR MUT) lead to glycoprotein maturation defects. Finally, by investigating the misfolding of the CALR glycoprotein client myeloperoxidase (MPO), we provide molecular proof of protein misfolding in the presence of homozygous CALR mutations.
    Keywords:  CP: Cancer; CP: Molecular biology; calreticulin; chaperone; glycoprotein; limited proteolysis-coupled mass spectrometry; myeloperoxidase; myeloproliferative neoplasm; protein folding; proteome
    DOI:  https://doi.org/10.1016/j.celrep.2022.111689
  6. Autophagy. 2022 Nov 23.
    FACS-mediated isolation of native autophagic vesicles.
    Daniel Schmitt, Süleyman Bozkurt, Pascale Henning-Domres, Heike Huesmann, Stefan Eimer, Laura Bindila, Christian Behrends, Emily Boyle, Florian Wilfling, Georg Tascher, Christian Münch, Christian Behl, Andreas Kern.
      Autophagosome isolation enables the thorough investigation of structural components and engulfed materials. Recently, we introduced a novel antibody-based FACS-mediated method for isolation of native macroautophagic/autophagic vesicles and confirmed the quality of the preparations. We performed phospholipidomic and proteomic analyses to characterize autophagic vesicle-associated phospholipids and protein cargoes under different autophagy conditions. Lipidomic analyses identified phosphoglycerides and sphingomyelins within autophagic vesicles and revealed that the lipid composition was unaffected by different rates of autophagosome formation. Proteomic analyses identified more than 4500 potential autophagy substrates and showed that in comparison to autophagic vesicles isolated under basal autophagy conditions, starvation only marginally affected the cargo profile. Proteasome inhibition, however, resulted in the enhanced degradation of ubiquitin-proteasome system components. Taken together, the novel isolation method enriched large quantities of autophagic vesicles and enabled detailed analyses of their lipid and cargo composition.
    Keywords:  autophagic vesicles; autophagy; cargo profiling; lipid profiling; vesicle isolation
    DOI:  https://doi.org/10.1080/15548627.2022.2151188
  7. Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01564-9. [Epub ahead of print]41(8): 111690
    Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.
    Yahyah Aman, Annmary Paul Erinjeri, Nikolaos Tataridas-Pallas, Rhianna Williams, Rachel Wellman, Hannah Chapman, John Labbadia.
      The age-related loss of protein homeostasis (proteostasis) is at the heart of numerous neurodegenerative diseases. Therefore, finding ways to preserve proteome integrity in aged cells may be a powerful way to promote long-term health. Here, we show that reducing the activity of a highly conserved mitochondrial outer membrane protein, MTCH-1/MTCH2, suppresses age-related proteostasis collapse in Caenorhabditis elegans without disrupting development, growth, or reproduction. Loss of MTCH-1 does not influence proteostasis capacity in aged tissues through previously described pathways but instead operates by reducing CED-4 levels. This results in the sequestration of HSP-90 by inactive CED-3, which in turn leads to an increase in HSF-1 activity, transcriptional remodeling of the proteostasis network, and maintenance of proteostasis capacity with age. Together, our findings reveal a role for programmed cell death factors in determining proteome health and suggest that inhibiting MTCH-1 activity in adulthood may safeguard the aging proteome and suppress age-related diseases.
    Keywords:  CP: Cell biology; Caenorhabditis elegans; HSF-1; HSP90; MTCH-1; aging; mitochondria; molecular chaperones; programmed cell death; protein homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111690
  8. Sci Adv. 2022 Nov 25. 8(47): eabo4116
    A deubiquitination module essential for Treg fitness in the tumor microenvironment.
    Elena Montauti, Samuel E Weinberg, Peng Chu, Shuvam Chaudhuri, Nikita L Mani, Radhika Iyer, Yuanzhang Zhou, Yusi Zhang, Changhong Liu, Chen Xin, Shana Gregory, Juncheng Wei, Yana Zhang, Wantao Chen, Zhaolin Sun, Ming Yan, Deyu Fang.
      The tumor microenvironment (TME) enhances regulatory T (Treg) cell stability and immunosuppressive functions through up-regulation of lineage transcription factor Foxp3, a phenomenon known as Treg fitness or adaptation. Here, we characterize previously unknown TME-specific cellular and molecular mechanisms underlying Treg fitness. We demonstrate that TME-specific stressors including transforming growth factor-β (TGF-β), hypoxia, and nutrient deprivation selectively induce two Foxp3-specific deubiquitinases, ubiquitin-specific peptidase 22 (Usp22) and Usp21, by regulating TGF-β, HIF, and mTOR signaling, respectively, to maintain Treg fitness. Simultaneous deletion of both USPs in Treg cells largely diminishes TME-induced Foxp3 up-regulation, alters Treg metabolic signatures, impairs Treg-suppressive function, and alleviates Treg suppression on cytotoxic CD8+ T cells. Furthermore, we developed the first Usp22-specific small-molecule inhibitor, which dramatically reduced intratumoral Treg Foxp3 expression and consequently enhanced antitumor immunity. Our findings unveil previously unappreciated mechanisms underlying Treg fitness and identify Usp22 as an antitumor therapeutic target that inhibits Treg adaptability in the TME.
    DOI:  https://doi.org/10.1126/sciadv.abo4116
  9. Nat Commun. 2022 Nov 24. 13(1): 7226
    Enhanced access to the human phosphoproteome with genetically encoded phosphothreonine.
    Jack M Moen, Kyle Mohler, Svetlana Rogulina, Xiaojian Shi, Hongying Shen, Jesse Rinehart.
      Protein phosphorylation is a ubiquitous post-translational modification used to regulate cellular processes and proteome architecture by modulating protein-protein interactions. The identification of phosphorylation events through proteomic surveillance has dramatically outpaced our capacity for functional assignment using traditional strategies, which often require knowledge of the upstream kinase a priori. The development of phospho-amino-acid-specific orthogonal translation systems, evolutionarily divergent aminoacyl-tRNA synthetase and tRNA pairs that enable co-translational insertion of a phospho-amino acids, has rapidly improved our ability to assess the physiological function of phosphorylation by providing kinase-independent methods of phosphoprotein production. Despite this utility, broad deployment has been hindered by technical limitations and an inability to reconstruct complex phopho-regulatory networks. Here, we address these challenges by optimizing genetically encoded phosphothreonine translation to characterize phospho-dependent kinase activation mechanisms and, subsequently, develop a multi-level protein interaction platform to directly assess the overlap of kinase and phospho-binding protein substrate networks with phosphosite-level resolution.
    DOI:  https://doi.org/10.1038/s41467-022-34980-5
  10. Antioxidants (Basel). 2022 Nov 14. pii: 2242. [Epub ahead of print]11(11):
    Resistance Training Modulates Reticulum Endoplasmic Stress, Independent of Oxidative and Inflammatory Responses, in Elderly People.
    Brisamar Estébanez, Nishant P Visavadiya, José E Vargas, Marta Rivera-Viloria, Andy V Khamoui, José A de Paz, Chun-Jung Huang.
      Aging is related to changes in the redox status, low-grade inflammation, and decreased endoplasmic reticulum unfolded protein response (UPR). Exercise has been shown to regulate the inflammatory response, balance redox homeostasis, and ameliorate the UPR. This work aimed to investigate the effects of resistance training on changes in the UPR, oxidative status, and inflammatory responses in peripheral blood mononuclear cells of elderly subjects. Thirty elderly subjects volunteered to participate in an 8-week resistance training program, and 11 youth subjects were included for basal assessments. Klotho, heat shock protein 60 (HSP60), oxidative marker expression (catalase, glutathione, lipid peroxidation, nuclear factor erythroid 2-related factor 2, protein carbonyls, reactive oxygen species, and superoxide dismutase 1 and 2), the IRE1 arm of UPR, and TLR4/TRAF6/pIRAK1 pathway activation were evaluated before and following training. No changes in the HSP60 and Klotho protein content, oxidative status markers, and TLR4/TRAF6/pIRAK1 pathway activation were found with exercise. However, an attenuation of the reduced pIRE1/IRE1 ratio was observed following training. Systems biology analysis showed that a low number of proteins (RPS27A, SYVN1, HSPA5, and XBP1) are associated with IRE1, where XBP1 and RPS27A are essential nodes according to the centrality analysis. Additionally, a gene ontology analysis confirms that endoplasmic reticulum stress is a key mechanism modulated by IRE1. These findings might partially support the modulatory effect of resistance training on the endoplasmic reticulum in the elderly.
    Keywords:  HSP60; IRE1; Klotho; UPR; aging; exercise; inflammaging; oxidative stress; strength exercise; systems biology
    DOI:  https://doi.org/10.3390/antiox11112242
  11. Autophagy. 2022 Nov 21. 1-18
    Autophagic lysosome reformation in health and disease.
    Randini Nanayakkara, Rajendra Gurung, Samuel J Rodgers, Matthew J Eramo, Georg Ramm, Christina A Mitchell, Meagan J McGrath.
      Lysosomes are the primary degradative compartment within cells and there have been significant advances over the past decade toward understanding how lysosome homeostasis is maintained. Lysosome repopulation ensures sustained autophagy function, a fundamental process that protects against disease. During macroautophagy/autophagy, cellular debris is sequestered into phagophores that mature into autophagosomes, which then fuse with lysosomes to generate autolysosomes in which contents are degraded. Autophagy cannot proceed without the sufficient generation of lysosomes, and this can be achieved via their de novo biogenesis. Alternatively, during autophagic lysosome reformation (ALR), lysosomes are generated via the recycling of autolysosome membranes. During this process, autolysosomes undergo significant membrane remodeling and scission to generate membrane fragments, that mature into functional lysosomes. By utilizing membranes already formed during autophagy, this facilitates an efficient pathway for re-deriving lysosomes, particularly under conditions of prolonged autophagic flux. ALR dysfunction is emerging as an important disease mechanism including for neurodegenerative disorders such as hereditary spastic paraplegia and Parkinson disease, neuropathies including Charcot-Marie-Tooth disease, lysosome storage disorders, muscular dystrophy, metabolic syndrome, and inflammatory and liver disorders. Here, we provide a comprehensive review of ALR, including an overview of its dynamic spatiotemporal regulation by MTOR and phosphoinositides, and the role ALR dysfunction plays in many diseases.
    Keywords:  Autophagic lysosome reformation; MTOR; PtdIns(4,5)P2; PtdIns4P; lysosome; phosphoinositide
    DOI:  https://doi.org/10.1080/15548627.2022.2128019
  12. Dev Cell. 2022 Nov 21. pii: S1534-5807(22)00760-2. [Epub ahead of print]57(22): 2584-2598.e11
    Autophagy promotes cell survival by maintaining NAD levels.
    Tetsushi Kataura, Lucia Sedlackova, Elsje G Otten, Ruchika Kumari, David Shapira, Filippo Scialo, Rhoda Stefanatos, Kei-Ichi Ishikawa, George Kelly, Elena Seranova, Congxin Sun, Dorothea Maetzel, Niall Kenneth, Sergey Trushin, Tong Zhang, Eugenia Trushina, Charles C Bascom, Ryan Tasseff, Robert J Isfort, John E Oblong, Satomi Miwa, Michael Lazarou, Rudolf Jaenisch, Masaya Imoto, Shinji Saiki, Manolis Papamichos-Chronakis, Ravi Manjithaya, Oliver D K Maddocks, Alberto Sanz, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components. Loss of autophagy in age-related human pathologies contributes to tissue degeneration through a poorly understood mechanism. Here, we identify an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD) levels, which are critical for cell survival. In respiring mouse fibroblasts with autophagy deficiency, loss of mitochondrial quality control was found to trigger hyperactivation of stress responses mediated by NADases of PARP and Sirtuin families. Uncontrolled depletion of the NAD(H) pool by these enzymes ultimately contributed to mitochondrial membrane depolarization and cell death. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient yeast, mouse fibroblasts, and human neurons. Our study provides a mechanistic link between autophagy and NAD metabolism and identifies targets for interventions in human diseases associated with autophagic, lysosomal, and mitochondrial dysfunction.
    Keywords:  DNA damage; NAD; PARP; Sirtuins; ageing; autophagy; metabolism; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.devcel.2022.10.008
  13. Nat Cancer. 2022 Nov 21.
    Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.
    Christopher J Halbrook, Galloway Thurston, Seth Boyer, Cecily Anaraki, Jennifer A Jiménez, Amy McCarthy, Nina G Steele, Samuel A Kerk, Hanna S Hong, Lin Lin, Fiona V Law, Catherine Felton, Lorenzo Scipioni, Peter Sajjakulnukit, Anthony Andren, Alica K Beutel, Rima Singh, Barbara S Nelson, Fran Van Den Bergh, Abigail S Krall, Peter J Mullen, Li Zhang, Sandeep Batra, Jennifer P Morton, Ben Z Stanger, Heather R Christofk, Michelle A Digman, Daniel A Beard, Andrea Viale, Ji Zhang, Howard C Crawford, Marina Pasca di Magliano, Claus Jorgensen, Costas A Lyssiotis.
      The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.
    DOI:  https://doi.org/10.1038/s43018-022-00463-1
  14. Cell Genom. 2022 Aug 10. pii: 100165. [Epub ahead of print]2(8):
    Spatial intra-tumor heterogeneity is associated with survival of lung adenocarcinoma patients.
    Hua-Jun Wu, Daniel Temko, Zoltan Maliga, Andre L Moreira, Emi Sei, Darlan Conterno Minussi, Jamie Dean, Charlotte Lee, Qiong Xu, Guillaume Hochart, Connor A Jacobson, Clarence Yapp, Denis Schapiro, Peter K Sorger, Erin H Seeley, Nicholas Navin, Robert J Downey, Franziska Michor.
      Intra-tumor heterogeneity (ITH) of human tumors is important for tumor progression, treatment response, and drug resistance. However, the spatial distribution of ITH remains incompletely understood. Here, we present spatial analysis of ITH in lung adenocarcinomas from 147 patients using multi-region mass spectrometry of >5,000 regions, single-cell copy number sequencing of ~2,000 single cells, and cyclic immunofluorescence of >10 million cells. We identified two distinct spatial patterns among tumors, termed clustered and random geographic diversification (GD). These patterns were observed in the same samples using both proteomic and genomic data. The random proteomic GD pattern, which is characterized by decreased cell adhesion and lower levels of tumor-interacting endothelial cells, was significantly associated with increased risk of recurrence or death in two independent patient cohorts. Our study presents comprehensive spatial mapping of ITH in lung adenocarcinoma and provides insights into the mechanisms and clinical consequences of GD.
    DOI:  https://doi.org/10.1016/j.xgen.2022.100165
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:27.