bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023‒08‒06
twenty-one papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Cancer cell plasticity during tumor progression, metastasis and response to therapy.
  2. Isolated pulmonary metastases in pancreatic ductal adenocarcinoma: a review of current evidence.
  3. Fibroblast-derived matrix models desmoplastic properties and forms a prognostic signature in cancer progression.
  4. CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.
  5. Nanoscale details of mitochondrial constriction revealed by cryo-electron tomography.
  6. Characterization and chemical modulation of p62/SQSTM1/Sequestosome-1 as an autophagic N-recognin.
  7. The ratio of key metabolic transcripts is a predictive biomarker of breast cancer metastasis to the lung.
  8. Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis.
  9. Central role of Tim17 in mitochondrial presequence protein translocation.
  10. Schwann cells regulate tumor cells and cancer-associated fibroblasts in the pancreatic ductal adenocarcinoma microenvironment.
  11. Is cancer an intelligent species?
  12. Pharmacological targeting of netrin-1 inhibits EMT in cancer.
  13. Proteogenomic analysis reveals RNA as a source for tumor-agnostic neoantigen identification.
  14. Parathyroid hormone related protein (PTHrP) in patients with pancreatic carcinoma and overt signs of disease progression and host tissue wasting.
  15. AI-based AlphaFold2 significantly expands the structural space of the autophagy pathway.
  16. The expanding organelle lipidomes: current knowledge and challenges.
  17. Pancreatic acinar heterogeneity hijacks carcinogenesis and homeostasis.
  18. Senescent cells form nuclear foci that contain the 26S proteasome.
  19. Immune vulnerabilities of mutant KRAS in pancreatic cancer.
  20. Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division.
  21. PIEZO2 in somatosensory neurons controls gastrointestinal transit.
  1. Nat Cancer. 2023 Aug 03.
    Cancer cell plasticity during tumor progression, metastasis and response to therapy.
    Andrea Pérez-González, Kevin Bévant, Cédric Blanpain.
      Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration following damage. Cell plasticity also contributes to pathological conditions, such as cancer, enabling cells to acquire new phenotypic and functional features by transiting across distinct cell states that contribute to tumor initiation, progression, metastasis and resistance to therapy. Here, we review the intrinsic and extrinsic mechanisms driving cell plasticity that promote tumor growth and proliferation as well as metastasis and drug tolerance. Finally, we discuss how cell plasticity could be exploited for anti-cancer therapy.
    DOI:  https://doi.org/10.1038/s43018-023-00595-y
  2. Cancer Biol Ther. 2023 Dec 31. 24(1): 2198479
    Isolated pulmonary metastases in pancreatic ductal adenocarcinoma: a review of current evidence.
    Orimisan Samuel Adekolujo, Ahsan Wahab, Maxwell Oluwole Akanbi, Tolutope Oyasiji, Borys Hrinczenko, Olatunji Boladale Alese.
      Despite recent advances in cancer therapeutics, pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year overall survival of only 10%. Since either at or within a few months of diagnosis, most patients with PDAC will present with metastatic disease, a more individualized approach to select patients who may benefit from more aggressive therapy has been suggested. Although studies have reported improved survival in PDAC and isolated pulmonary metastasis (ISP) compared to extrapulmonary metastases, such findings remain controversial. Furthermore, the added benefit of pulmonary metastasectomy and other lung-directed therapies remains unclear. In this review, we discuss the metastatic pattern of PDAC, evaluate the available evidence in the literature for improved survival in PDAC and ISP, evaluate the evidence for the added benefit of pulmonary metastasectomy and other lung-directed therapies, identify prognostic factors for survival, discuss the biological basis for the reported improved survival and identify areas for further research.
    Keywords:  Lung resection; Pancreatic ductal adenocarcinoma; isolated pulmonary metastases; pulmonary metastasectomy; survival
    DOI:  https://doi.org/10.1080/15384047.2023.2198479
  3. Front Immunol. 2023 ;14 1154528
    Fibroblast-derived matrix models desmoplastic properties and forms a prognostic signature in cancer progression.
    Maria Rafaeva, Adina R D Jensen, Edward R Horton, Kamilla W Zornhagen, Jan E Strøbech, Lutz Fleischhauer, Alejandro E Mayorca-Guiliani, Sebastian R Nielsen, Dina S Grønseth, Filip Kuś, Erwin M Schoof, Luis Arnes, Manuel Koch, Hauke Clausen-Schaumann, Valerio Izzi, Raphael Reuten, Janine T Erler.
      The desmoplastic reaction observed in many cancers is a hallmark of disease progression and prognosis, particularly in breast and pancreatic cancer. Stromal-derived extracellular matrix (ECM) is significantly altered in desmoplasia, and as such plays a critical role in driving cancer progression. Using fibroblast-derived matrices (FDMs), we show that cancer cells have increased growth on cancer associated FDMs, when compared to FDMs derived from non-malignant tissue (normal) fibroblasts. We assess the changes in ECM characteristics from normal to cancer-associated stroma at the primary tumor site. Compositional, structural, and mechanical analyses reveal significant differences, with an increase in abundance of core ECM proteins, coupled with an increase in stiffness and density in cancer-associated FDMs. From compositional changes of FDM, we derived a 36-ECM protein signature, which we show matches in large part with the changes in pancreatic ductal adenocarcinoma (PDAC) tumor and metastases progression. Additionally, this signature also matches at the transcriptomic level in multiple cancer types in patients, prognostic of their survival. Together, our results show relevance of FDMs for cancer modelling and identification of desmoplastic ECM components for further mechanistic studies.
    Keywords:  breast cancer; desmoplasia; extracellular matrix; fibroblasts; mechanics; models; pancreatic cancer
    DOI:  https://doi.org/10.3389/fimmu.2023.1154528
  4. Science. 2023 Aug 04. 381(6657): 515-524
    CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.
    Ruben Bill, Pratyaksha Wirapati, Marius Messemaker, Whijae Roh, Beatrice Zitti, Florent Duval, Máté Kiss, Jong Chul Park, Talia M Saal, Jan Hoelzl, David Tarussio, Fabrizio Benedetti, Stéphanie Tissot, Lana Kandalaft, Marco Varrone, Giovanni Ciriello, Thomas A McKee, Yan Monnier, Maxime Mermod, Emily M Blaum, Irena Gushterova, Anna L K Gonye, Nir Hacohen, Gad Getz, Thorsten R Mempel, Allon M Klein, Ralph Weissleder, William C Faquin, Peter M Sadow, Derrick Lin, Sara I Pai, Moshe Sade-Feldman, Mikael J Pittet.
      Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.
    DOI:  https://doi.org/10.1126/science.ade2292
  5. Biophys J. 2023 Aug 01. pii: S0006-3495(23)00481-2. [Epub ahead of print]
    Nanoscale details of mitochondrial constriction revealed by cryo-electron tomography.
    Shrawan Kumar Mageswaran, Danielle Ann Grotjahn, Xiangrui Zeng, Benjamin Asher Barad, Michaela Medina, My Hanh Hoang, Megan J Dobro, Yi-Wei Chang, Min Xu, Wei Yuan Yang, Grant J Jensen.
      Mitochondria adapt to changing cellular environments, stress stimuli, and metabolic demands through dramatic morphological remodeling of their shape, and thus function. Such mitochondrial dynamics is often dependent on cytoskeletal filament interactions. However, the precise organization of these filamentous assemblies remains speculative. Here, we apply cryogenic electron tomography to directly image the nanoscale architecture of the cytoskeletal-membrane interactions involved in mitochondrial dynamics in response to damage. We induced mitochondrial damage via membrane depolarization, a cellular stress associated with mitochondrial fragmentation and mitophagy. We find that, in response to acute membrane depolarization, mammalian mitochondria predominantly organize into tubular morphology that abundantly displays constrictions. We observe long bundles of both unbranched actin and septin filaments enriched at these constrictions. We also observed septin-microtubule interactions at these sites and elsewhere suggesting that these two filaments guide each other in the cytosolic space. Together, our results provide empirical parameters for the architecture of mitochondrial constriction factors to validate/refine existing models and inform the development of new ones.
    DOI:  https://doi.org/10.1016/j.bpj.2023.07.030
  6. Methods Enzymol. 2023 ;pii: S0076-6879(23)00061-7. [Epub ahead of print]686 235-265
    Characterization and chemical modulation of p62/SQSTM1/Sequestosome-1 as an autophagic N-recognin.
    Su Jin Lee, Hye Yeon Kim, Min Ju Lee, Su Bin Kim, Yong Tae Kwon, Chang Hoon Ji.
      In the Arg/N-degron pathway, single N-terminal (Nt) residues function as N-degrons recognized by UBR box-containing N-recognins that induce substrate ubiquitination and proteasomal degradation. Recent studies led to the discovery of the autophagic Arg/N-degron pathway, in which the autophagic receptor p62/SQSTM1/Sequestosome-1 acts as an N-recognin that binds the Nt-Arg and other destabilizing residues as N-degrons. Upon binding to Nt-Arg, p62 undergoes self-polymerization associated with its cargoes, accelerating the macroautophagic delivery of p62-cargo complexes to autophagosomes leading to degradation by lysosomal hydrolases. This autophagic mechanism is emerging as an important pathway that modulates the lysosomal degradation of various biomaterial ranging from protein aggregates and subcellular organelles to invading pathogens. Chemical mimics of the physiological N-degrons were developed to exert therapeutic efficacy in pathophysiological processes associated with neurodegeneration and other related diseases. Here, we describe the methods to monitor the activities of p62 in a dual role as an N-recognin and an autophagic receptor. The topic includes self-polymerization (for cargo condensation), its interaction with LC3 on autophagic membranes (for cargo targeting), and the degradation of p62-cargo complexes by lysosomal hydrolases. We also discuss the development and use of small molecule mimics of N-degrons that modulate p62-dependent macroautophagy in biological and pathophysiological processes.
    Keywords:  Autophagy flux assay; Autophagy-targeting ligand (ATL); Colocalization assay; In vitro oligomerization assay; Molecular modeling; N-degron pathway; N-terminal arginylation; Selective autophagy; Targeted protein degradation (TPD); p62/SQSTM1/Sequestosome-1
    DOI:  https://doi.org/10.1016/bs.mie.2023.02.005
  7. Cancer Res. 2023 Aug 01. pii: CAN-23-0153. [Epub ahead of print]
    The ratio of key metabolic transcripts is a predictive biomarker of breast cancer metastasis to the lung.
    Deepti Mathur, Chen Liao, Wendy Lin, Alessandro La Ferlita, Salvatore Alaimo, Samuel Taylor, Yi Zhong, Christine Iacobuzio-Donahue, Alfredo Ferro, Joao B Xavier.
      Understanding the rewired metabolism underlying organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of metastatic disease. Here, we used a systems biology approach to compare metabolic fluxes used by parental breast cancer cells and their brain- and lung-homing derivatives. Divergent lineages had distinct, heritable metabolic fluxes. Lung-homing cells maintained high glycolytic flux despite low levels of glycolytic intermediates, constitutively activating a pathway sink into lactate. This strong Warburg effect was associated with a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) expression, which correlated with lung metastasis in patients with breast cancer. While feature classification models trained on clinical characteristics alone were unable to predict tropism, the LDH/PDH ratio was a significant predictor of metastasis to the lung but not to other organs, independent of other transcriptomic signatures. High lactate efflux was also a trait in lung-homing metastatic pancreatic cancer cells, suggesting that lactate production may be a convergent phenotype in lung metastasis. Together, these analyses highlight the essential role that metabolism plays in organ-specific cancer metastasis and identify a putative biomarker for predicting lung metastasis in breast cancer patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0153
  8. Cell Stem Cell. 2023 Aug 03. pii: S1934-5909(23)00247-3. [Epub ahead of print]30(8): 1091-1109.e7
    Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis.
    Zhengyu Jiang, Feijing Wu, Pasquale Laise, Tanaka Takayuki, Fu Na, Woosook Kim, Hiroki Kobayashi, Wenju Chang, Ryota Takahashi, Giovanni Valenti, Masaki Sunagawa, Ruth A White, Marina Macchini, Bernhard W Renz, Moritz Middelhoff, Yoku Hayakawa, Zinaida A Dubeykovskaya, Xiangtian Tan, Timothy H Chu, Karan Nagar, Yagnesh Tailor, Bryana R Belin, Akanksha Anand, Samuel Asfaha, Michael O Finlayson, Alina C Iuga, Andrea Califano, Timothy C Wang.
      While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreERT2-targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2+ cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic KrasG12D-targeted Tff2+ cells are resistant to PDAC initiation. However, KrasG12D activation in Tff2+ cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2+ cells prior to KrasG12D activation in Mist1+ acinar or Dclk1+ FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis.
    Keywords:  cell ablation; lineage tracing; pancreas; pancreatic ductal carcinoma; progenitor cells; regeneration; transit-amplifying cells; trefoil factor 2
    DOI:  https://doi.org/10.1016/j.stem.2023.07.002
  9. Nature. 2023 Aug 01.
    Central role of Tim17 in mitochondrial presequence protein translocation.
    Laura F Fielden, Jakob D Busch, Sandra G Merkt, Iniyan Ganesan, Conny Steiert, Hanna B Hasselblatt, Jon V Busto, Christophe Wirth, Nicole Zufall, Sibylle Jungbluth, Katja Noll, Julia M Dung, Ludmila Butenko, Karina von der Malsburg, Hans-Georg Koch, Carola Hunte, Martin van der Laan, Nils Wiedemann.
      The presequence translocase of the mitochondrial inner membrane (TIM23) represents the major route for the import of nuclear-encoded proteins into mitochondria1,2. About 60% of more than 1,000 different mitochondrial proteins are synthesised with amino-terminal targeting signals, termed presequences, which form positively charged amphiphilic α-helices3,4. TIM23 sorts the presequence proteins into the inner membrane or matrix. Various views including regulatory and coupling functions have been reported on the essential TIM23 subunit Tim175-7. We mapped the interaction of Tim17 with matrix-targeted and inner membrane-sorted preproteins during translocation in the native membrane environment. We show that Tim17 contains conserved negative charges close to the intermembrane space side of the bilayer, which are essential to initiate presequence protein translocation along a distinct transmembrane cavity of Tim17 for both classes of preproteins. The amphiphilic character of mitochondrial presequences directly matches this Tim17-dependent translocation mechanism. This mechanism permits direct lateral release of transmembrane segments of inner membrane-sorted precursors into the inner membrane.
    DOI:  https://doi.org/10.1038/s41586-023-06477-8
  10. Nat Commun. 2023 07 31. 14(1): 4600
    Schwann cells regulate tumor cells and cancer-associated fibroblasts in the pancreatic ductal adenocarcinoma microenvironment.
    Meilin Xue, Youwei Zhu, Yongsheng Jiang, Lijie Han, Minmin Shi, Rui Su, Liwen Wang, Cheng Xiong, Chaofu Wang, Ting Wang, Shijie Deng, Dong Wu, Yizhi Cao, Lei Dong, Fan Bai, Shulin Zhao, Xiaxing Deng, Chenghong Peng, Hongwei Li, Jianjun Chen, Baiyong Shen, Lingxi Jiang, Hao Chen.
      Neuropathy is a feature more frequently observed in pancreatic ductal adenocarcinoma (PDAC) than other tumors. Schwann cells, the most prevalent cell type in peripheral nerves, migrate toward tumor cells and associate with poor prognosis in PDAC. To unveil the effects of Schwann cells on the neuro-stroma niche, here we perform single-cell RNA-sequencing and microarray-based spatial transcriptome analysis of PDAC tissues. Results suggest that Schwann cells may drive tumor cells and cancer-associated fibroblasts (CAFs) to more malignant subtypes: basal-like and inflammatory CAFs (iCAFs), respectively. Moreover, in vitro and in vivo assays demonstrate that Schwann cells enhance the proliferation and migration of PDAC cells via Midkine signaling and promote the switch of CAFs to iCAFs via interleukin-1α. Culture of tumor cells and CAFs with Schwann cells conditioned medium accelerates PDAC progression. Thus, we reveal that Schwann cells induce malignant subtypes of tumor cells and CAFs in the PDAC milieu.
    DOI:  https://doi.org/10.1038/s41467-023-40314-w
  11. Cancer Metastasis Rev. 2023 Aug 04.
    Is cancer an intelligent species?
    Chiara Nicolazzo, Federica Francescangeli, Valentina Magri, Alessandro Giuliani, Ann Zeuner, Paola Gazzaniga.
      Some relevant emerging properties of intelligent systems are "adaptation to a changing environment," "reaction to unexpected situations," "capacity of problem solving," and "ability to communicate." Single cells have remarkable abilities to adapt, make adequate context-dependent decision, take constructive actions, and communicate, thus theoretically meeting all the above-mentioned requirements. From a biological point of view, cancer can be viewed as an invasive species, composed of cells that move from primary to distant sites, being continuously exposed to changes in the environmental conditions. Blood represents the first hostile habitat that a cancer cell encounters once detached from the primary site, so that cancer cells must rapidly carry out multiple adaptation strategies to survive. The aim of this review was to deepen the adaptation mechanisms of cancer cells in the blood microenvironment, particularly referring to four adaptation strategies typical of animal species (phenotypic adaptation, metabolic adaptation, niche adaptation, and collective adaptation), which together define the broad concept of biological intelligence. We provided evidence that the required adaptations (either structural, metabolic, and related to metastatic niche formation) and "social" behavior are useful principles allowing putting into a coherent frame many features of circulating cancer cells. This interpretative frame is described by the comparison with analog behavioral traits typical of various animal models.
    Keywords:  Adaptation; Circulating tumor cells; EMT; Intelligence
    DOI:  https://doi.org/10.1007/s10555-023-10123-0
  12. Nature. 2023 Aug 02.
    Pharmacological targeting of netrin-1 inhibits EMT in cancer.
    Justine Lengrand, Ievgenia Pastushenko, Sebastiaan Vanuytven, Yura Song, David Venet, Rahul M Sarate, Melanie Bellina, Virginie Moers, Alice Boinet, Alejandro Sifrim, Nicolas Rama, Benjamin Ducarouge, Jens Van Herck, Christine Dubois, Samuel Scozzaro, Sophie Lemaire, Sarah Gieskes, Sophie Bonni, Amandine Collin, Nicolas Braissand, Justine Allard, Egor Zindy, Christine Decaestecker, Christos Sotiriou, Isabelle Salmon, Patrick Mehlen, Thierry Voet, Agnès Bernet, Cédric Blanpain.
      Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy1-7. Although great progress has been made in understanding the role of EMT and its regulatory mechanisms in cancer, no therapeutic strategy to pharmacologically target EMT has been identified. Here we found that netrin-1 is upregulated in a primary mouse model of skin squamous cell carcinoma (SCC) exhibiting spontaneous EMT. Pharmacological inhibition of netrin-1 by administration of NP137, a netrin-1-blocking monoclonal antibody currently used in clinical trials in human cancer (ClinicalTrials.gov identifier NCT02977195 ), decreased the proportion of EMT tumour cells in skin SCC, decreased the number of metastases and increased the sensitivity of tumour cells to chemotherapy. Single-cell RNA sequencing revealed the presence of different EMT states, including epithelial, early and late hybrid EMT, and full EMT states, in control SCC. By contrast, administration of NP137 prevented the progression of cancer cells towards a late EMT state and sustained tumour epithelial states. Short hairpin RNA knockdown of netrin-1 and its receptor UNC5B in EPCAM+ tumour cells inhibited EMT in vitro in the absence of stromal cells and regulated a common gene signature that promotes tumour epithelial state and restricts EMT. To assess the relevance of these findings to human cancers, we treated mice transplanted with the A549 human cancer cell line-which undergoes EMT following TGFβ1 administration8,9-with NP137. Netrin-1 inhibition decreased EMT in these transplanted A549 cells. Together, our results identify a pharmacological strategy for targeting EMT in cancer, opening up novel therapeutic interventions for anti-cancer therapy.
    DOI:  https://doi.org/10.1038/s41586-023-06372-2
  13. Nat Commun. 2023 08 02. 14(1): 4632
    Proteogenomic analysis reveals RNA as a source for tumor-agnostic neoantigen identification.
    Celina Tretter, Niklas de Andrade Krätzig, Matteo Pecoraro, Sebastian Lange, Philipp Seifert, Clara von Frankenberg, Johannes Untch, Gabriela Zuleger, Mathias Wilhelm, Daniel P Zolg, Florian S Dreyer, Eva Bräunlein, Thomas Engleitner, Sebastian Uhrig, Melanie Boxberg, Katja Steiger, Julia Slotta-Huspenina, Sebastian Ochsenreither, Nikolas von Bubnoff, Sebastian Bauer, Melanie Boerries, Philipp J Jost, Kristina Schenck, Iska Dresing, Florian Bassermann, Helmut Friess, Daniel Reim, Konrad Grützmann, Katrin Pfütze, Barbara Klink, Evelin Schröck, Bernhard Haller, Bernhard Kuster, Matthias Mann, Wilko Weichert, Stefan Fröhling, Roland Rad, Michael Hiltensperger, Angela M Krackhardt.
      Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.
    DOI:  https://doi.org/10.1038/s41467-023-39570-7
  14. Transl Oncol. 2023 Aug 02. pii: S1936-5233(23)00138-9. [Epub ahead of print]36 101752
    Parathyroid hormone related protein (PTHrP) in patients with pancreatic carcinoma and overt signs of disease progression and host tissue wasting.
    Britt-Marie Iresjö, Serkan Kir, Kent Lundholm.
      BACKGROUND: Cancer-cachexia is a complex syndrome secondary to physiological mechanisms related to classical hormone and immune alterations, where contributions of neuro-endocrine involvement have been less evaluated. Therefore, the aim of our study was to explore relationships between PTHrP and whole body metabolism in patients with progressive pancreatic carcinoma; relevant to "fat tissue browning".METHODS: Patient serum samples and clinical information were retrieved from earlier translational projects (1995-2005), at Sahlgrenska University Hospital in Gothenburg. Blood PTHrP levels were determined at Harvard medical School (2014). Patient data included: medical history, clinical laboratory tests, food diaries, resting metabolic expenditure, body composition, exercise capacity, Health-Related Quality of Life (SF-36) and mental disorders (HAD-scales).
    RESULTS: Serum PTHrP was detectable in 17 % of all samples without significance to tumor stage. PTHrP-negativity at inclusion remained during follow-up. Mean PTHrP concentration was 262±274 pg/ml, without sex difference and elevation over time. PTHrP-positive and negative patients experienced similar body weight loss (%) at inclusion, with a trend to deviate at follow ups (16.8±8.2% vs. 13.1±8.2%, p<0.06), where PTHrP concentrations showed correlations to weight loss, handgrip strength and Karnofsky performance, without difference in exercise capacity. PTHrP-positivity was related to increased whole body fat oxidation (p<0.006-0.01) and reduced carbohydrate oxidation (p<0.01-0.03), independently of peripheral lipolysis. Metabolic alterations in PTHrP-positive patients were related to reduced Health Related Quality of life (SF: p<0.08, MH: p<0.02), and increased anxiety and depression (HAD 1-7: p<0.004; HAD 8-14: p<0.008).
    CONCLUSION: Serum PTHrP positivity in patients with pancreatic carcinoma was related to altered whole body oxidative metabolism; perhaps induced by "browning" of fat cells?
    Keywords:  Cachexia; Oxidative metabolism; PTHrP; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.tranon.2023.101752
  15. Autophagy. 2023 Jul 30. 1-20
    AI-based AlphaFold2 significantly expands the structural space of the autophagy pathway.
    Nidhi Malhotra, Shantanu Khatri, Ajit Kumar, Akanksha Arun, Purba Daripa, Saman Fatihi, Sureshkumar Venkadesan, Niyati Jain, Lipi Thukral.
      ABBREVIATIONS: AF2: AlphaFold2; AF2-Mult: AlphaFold2 multimer; ATG: autophagy-related; CTD: C-terminal domain; ECTD: extreme C-terminal domain; FR: flexible region; MD: molecular dynamics; NTD: N-terminal domain; pLDDT: predicted local distance difference test; UBL: ubiquitin-like.
    Keywords:  ATG7-ATG10 complex; AlphaFold2; autophagic interactome; autophagy; molecular dynamics simulations
    DOI:  https://doi.org/10.1080/15548627.2023.2238578
  16. Cell Mol Life Sci. 2023 Aug 02. 80(8): 237
    The expanding organelle lipidomes: current knowledge and challenges.
    Maria J Sarmento, Alicia Llorente, Toni Petan, Denis Khnykin, Iuliana Popa, Matea Nikolac Perkovic, Marcela Konjevod, Morana Jaganjac.
      Lipids in cell membranes and subcellular compartments play essential roles in numerous cellular processes, such as energy production, cell signaling and inflammation. A specific organelle lipidome is characterized by lipid synthesis and metabolism, intracellular trafficking, and lipid homeostasis in the organelle. Over the years, considerable effort has been directed to the identification of the lipid fingerprints of cellular organelles. However, these fingerprints are not fully characterized due to the large variety and structural complexity of lipids and the great variability in the abundance of different lipid species. The process becomes even more challenging when considering that the lipidome differs in health and disease contexts. This review summarizes the information available on the lipid composition of mammalian cell organelles, particularly the lipidome of the nucleus, mitochondrion, endoplasmic reticulum, Golgi apparatus, plasma membrane and organelles in the endocytic pathway. The lipid compositions of extracellular vesicles and lamellar bodies are also described. In addition, several examples of subcellular lipidome dynamics under physiological and pathological conditions are presented. Finally, challenges in mapping organelle lipidomes are discussed.
    Keywords:  Cellular organelles; Lipidomics; Lipids; Mass spectrometry; Subcellular fractionation
    DOI:  https://doi.org/10.1007/s00018-023-04889-3
  17. Cell Stem Cell. 2023 Aug 03. pii: S1934-5909(23)00252-7. [Epub ahead of print]30(8): 1003-1005
    Pancreatic acinar heterogeneity hijacks carcinogenesis and homeostasis.
    Michael Karl Melzer, Alexander Kleger.
      In this issue, Jiang and colleagues employ multiple lineage-tracing approaches to elaborate on the role of Tff2+ transit-amplifying progenitor cells in the pancreatic acinar compartment of mice. This work provides insights into the steady-state homeostasis and tumor-suppressive features of certain progenitor cells and presents findings on acinar cell heterogeneity.
    DOI:  https://doi.org/10.1016/j.stem.2023.07.008
  18. Cell Rep. 2023 Aug 01. pii: S2211-1247(23)00891-4. [Epub ahead of print] 112880
    Senescent cells form nuclear foci that contain the 26S proteasome.
    Tomohiro Iriki, Hiroaki Iio, Shu Yasuda, Shun Masuta, Masakazu Kato, Hidetaka Kosako, Shoshiro Hirayama, Akinori Endo, Fumiaki Ohtake, Mako Kamiya, Yasuteru Urano, Yasushi Saeki, Jun Hamazaki, Shigeo Murata.
      The proteasome plays a central role in intracellular protein degradation. Age-dependent decline in proteasome activity is associated with cellular senescence and organismal aging; however, the mechanism by which the proteasome plays a role in senescent cells remains elusive. Here, we show that nuclear foci that contain the proteasome and exhibit liquid-like properties are formed in senescent cells. The formation of senescence-associated nuclear proteasome foci (SANPs) is dependent on ubiquitination and RAD23B, similar to previously known nuclear proteasome foci, but also requires proteasome activity. RAD23B knockdown suppresses SANP formation and increases mitochondrial activity, leading to reactive oxygen species production without affecting other senescence traits such as cell-cycle arrest and cell morphology. These findings suggest that SANPs are an important feature of senescent cells and uncover a mechanism by which the proteasome plays a role in senescent cells.
    Keywords:  CP: Cell biology; CP: Molecular biology; cell senescence; liquid-liquid phase separation; mitochondria; nuclear body; proteasome; ubiquitin
    DOI:  https://doi.org/10.1016/j.celrep.2023.112880
  19. Trends Cancer. 2023 Jul 29. pii: S2405-8033(23)00131-0. [Epub ahead of print]
    Immune vulnerabilities of mutant KRAS in pancreatic cancer.
    Noah C Cheng, Robert H Vonderheide.
      The 40-year desire to target the mutant Kirsten rat sarcoma (KRAS) gene (mKRAS) therapeutically is being realized with more and more broadly applicable and tumor-specific small-molecule inhibitors. Immunologically, mKRAS has equal desirability as a target. Tumor KRAS signaling plays a large role in shaping the immunosuppressive nature of the tumor microenvironment, especially in pancreatic cancer, leaving mKRAS inhibitors with potentially powerful immune modulatory capabilities that could be exploited in immunological-oncological combinations. mKRAS is itself an immunological antigen, a 'shared neoepitope' linked to the oncogenic process, validated biochemically and immunologically. Novel approaches in the clinic are taking advantage of the fact that mKRAS peptides are naturally processed and presented in tumors by the major histocompatibility complex (MHC).
    Keywords:  TCR therapies; immune response; inhibitors; mutant KRAS; pancreatic cancer; vaccines
    DOI:  https://doi.org/10.1016/j.trecan.2023.07.004
  20. Nat Immunol. 2023 Aug 03.
    Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division.
    Michael W Rudloff, Paul Zumbo, Natalie R Favret, Jessica J Roetman, Carlos R Detrés Román, Megan M Erwin, Kristen A Murray, Sriya T Jonnakuti, Friederike Dündar, Doron Betel, Mary Philip.
      Tumor-specific CD8+ T cells (TST) in patients with cancer are dysfunctional and unable to halt cancer progression. TST dysfunction, also known as exhaustion, is thought to be driven by chronic T cell antigen receptor (TCR) stimulation over days to weeks. However, we know little about the interplay between CD8+ T cell function, cell division and epigenetic remodeling within hours of activation. Here, we assessed early CD8+ T cell differentiation, cell division, chromatin accessibility and transcription in tumor-bearing mice and acutely infected mice. Surprisingly, despite robust activation and proliferation, TST had near complete effector function impairment even before undergoing cell division and had acquired hallmark chromatin accessibility features previously associated with later dysfunction/exhaustion. Moreover, continued tumor/antigen exposure drove progressive epigenetic remodeling, 'imprinting' the dysfunctional state. Our study reveals the rapid divergence of T cell fate choice before cell division in the context of tumors versus infection.
    DOI:  https://doi.org/10.1038/s41590-023-01578-y
  21. Cell. 2023 Aug 03. pii: S0092-8674(23)00739-0. [Epub ahead of print]186(16): 3386-3399.e15
    PIEZO2 in somatosensory neurons controls gastrointestinal transit.
    M Rocio Servin-Vences, Ruby M Lam, Alize Koolen, Yu Wang, Dimah N Saade, Meaghan Loud, Halil Kacmaz, Suzanne Frausto, Yunxiao Zhang, Arthur Beyder, Kara L Marshall, Carsten G Bönnemann, Alexander T Chesler, Ardem Patapoutian.
      The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence of food and help digestion by mechanically breaking down and propelling gut content. Mechanical sensing in the gut is thought to be essential for regulating motility; however, the identity of the neuronal populations, the molecules involved, and the functional consequences of this sensation are unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root, but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in the stomach, small intestine, and colon. Indeed, Piezo2 is directly required to detect colon distension in vivo. Our study unveils the mechanosensory mechanisms that regulate the transit of luminal contents throughout the gut, which is a critical process to ensure proper digestion, nutrient absorption, and waste removal.
    Keywords:  PIEZO2 deficiency; Piezo2; dorsal root ganglia; gastrointestinal tract; gut motility; gut transit; interoception; mechanosensation; sensory neurons; spinal innervation
    DOI:  https://doi.org/10.1016/j.cell.2023.07.006
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