bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023‒02‒12
23 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Nutrient transporters: connecting cancer metabolism to therapeutic opportunities.
  2. Application of high-throughput single-nucleus DNA sequencing in pancreatic cancer.
  3. IL-17A-producing CD8+ T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts.
  4. Autophagy: A challengeable paradox in cancer treatment.
  5. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis.
  6. Open-source curation of a pancreatic ductal adenocarcinoma gene expression analysis platform (pdacR) supports a two-subtype model.
  7. Addition of losartan to FOLFIRINOX and chemoradiation reduces immunosuppression-associated genes, Tregs and FOXP3+ cancer cells in locally advanced pancreatic cancer.
  8. Bilateral JNK activation is a hallmark of interface surveillance and promotes elimination of aberrant cells.
  9. Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.
  10. Allosteric regulation of CAD modulates de novo pyrimidine synthesis during the cell cycle.
  11. Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms.
  12. Targeting galectin-driven regulatory circuits in cancer and fibrosis.
  13. Human atlastins are sufficient to drive the fusion of liposomes with a physiological lipid composition.
  14. The Impact of Molecular Subtyping on Pathological Staging of Pancreatic Cancer.
  15. Developing SHP2-based combination therapy for KRAS-amplified cancer.
  16. Preclinical models to study patient-derived circulating tumor cells and metastasis.
  17. Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution.
  18. Discovery of Targets for Immune-Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha.
  19. mNeuCode Empowers Targeted Proteome Analysis of Arginine Dimethylation.
  20. G-quadruplex ligands as potent regulators of lysosomes.
  21. Pervasiveness of HLA allele-specific expression loss across tumor types.
  22. Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo.
  23. Utility of Comprehensive Genomic Profiling Tests for Patients with Incurable Pancreatic Cancer in Clinical Practice.
  1. Oncogene. 2023 Feb 04.
    Nutrient transporters: connecting cancer metabolism to therapeutic opportunities.
    Zeribe Chike Nwosu, Mun Gu Song, Marina Pasca di Magliano, Costas A Lyssiotis, Sung Eun Kim.
      Cancer cells rely on certain extracellular nutrients to sustain their metabolism and growth. Solute carrier (SLC) transporters enable cells to acquire extracellular nutrients or shuttle intracellular nutrients across organelles. However, the function of many SLC transporters in cancer is unknown. Determining the key SLC transporters promoting cancer growth could reveal important therapeutic opportunities. Here we summarize recent findings and knowledge gaps on SLC transporters in cancer. We highlight existing inhibitors for studying these transporters, clinical trials on treating cancer by blocking transporters, and compensatory transporters used by cancer cells to evade treatment. We propose targeting transporters simultaneously or in combination with targeted therapy or immunotherapy as alternative strategies for effective cancer therapy.
    DOI:  https://doi.org/10.1038/s41388-023-02593-x
  2. Nat Commun. 2023 Feb 10. 14(1): 749
    Application of high-throughput single-nucleus DNA sequencing in pancreatic cancer.
    Haochen Zhang, Elias-Ramzey Karnoub, Shigeaki Umeda, Ronan Chaligné, Ignas Masilionis, Caitlin A McIntyre, Palash Sashittal, Akimasa Hayashi, Amanda Zucker, Katelyn Mullen, Jungeui Hong, Alvin Makohon-Moore, Christine A Iacobuzio-Donahue.
      Despite insights gained by bulk DNA sequencing of cancer it remains challenging to resolve the admixture of normal and tumor cells, and/or of distinct tumor subclones; high-throughput single-cell DNA sequencing circumvents these and brings cancer genomic studies to higher resolution. However, its application has been limited to liquid tumors or a small batch of solid tumors, mainly because of the lack of a scalable workflow to process solid tumor samples. Here we optimize a highly automated nuclei extraction workflow that achieves fast and reliable targeted single-nucleus DNA library preparation of 38 samples from 16 pancreatic ductal adenocarcinoma patients, with an average library yield per sample of 2867 single nuclei. We demonstrate that this workflow not only performs well using low cellularity or low tumor purity samples but reveals genomic evolution patterns of pancreatic ductal adenocarcinoma as well.
    DOI:  https://doi.org/10.1038/s41467-023-36344-z
  3. Gut. 2023 Feb 09. pii: gutjnl-2022-327855. [Epub ahead of print]
    IL-17A-producing CD8+ T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts.
    Felix Simon Ruben Picard, Veronika Lutz, Anna Brichkina, Felix Neuhaus, Teresa Ruckenbrod, Anna Hupfer, Hartmann Raifer, Matthias Klein, Tobias Bopp, Petra Ina Pfefferle, Rajkumar Savai, Immo Prinz, Ari Waisman, Sonja Moos, Hyun-Dong Chang, Stefan Heinrich, Detlef K Bartsch, Malte Buchholz, Shiv Singh, Mengyu Tu, Lukas Klein, Christian Bauer, Robert Liefke, Andreas Burchert, Ho-Ryun Chung, Philipp Mayer, Thomas M Gress, Matthias Lauth, Matthias Gaida, Magdalena Huber.
      OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8+ T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC.DESIGN: Infiltration of Tc17 cells in PDAC tissue was correlated with patient overall survival and tumour stage. Wild-type (WT) or Il17ra-/- quiescent pancreatic stellate cells (qPSC) were exposed to conditional media obtained from Tc17 cells (Tc17-CM); moreover, co-culture of Tc17-CM-induced inflammatory (i)CAF (Tc17-iCAF) with tumour cells was performed. IL-17A/F-, IL-17RA-, RAG1-deficient and Foxn1nu/nu mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models.
    RESULTS: Increased abundance of Tc17 cells highly correlated with reduced survival and advanced tumour stage in PDAC. Tc17-CM induced iCAF differentiation as assessed by the expression of iCAF-associated genes via synergism of IL-17A and TNF. Accordingly, IL-17RA controlled the responsiveness of qPSC to Tc17-CM. Pancreatic tumour cells co-cultured with Tc17-iCAF displayed enhanced proliferation and increased expression of genes implicated in proliferation, metabolism and protection from apoptosis. Tc17-iCAF accelerated growth of mouse and human tumours in Rag1-/- and Foxn1nu/nu mice, respectively. Finally, Il17ra-expressed by fibroblasts was required for Tc17-driven tumour growth in vivo.
    CONCLUSIONS: We identified Tc17 as a novel protumourigenic CD8+ T-cell subtype in PDAC, which accelerated tumour growth via IL-17RA-dependent stroma modification. We described a crosstalk between three cell types, Tc17, fibroblasts and tumour cells, promoting PDAC progression, which resulted in poor prognosis for patients.
    Keywords:  cancer immunobiology; cytokines; immune response; inflammatory mechanisms; pancreatic cancer
    DOI:  https://doi.org/10.1136/gutjnl-2022-327855
  4. Cancer Med. 2023 Feb 09.
    Autophagy: A challengeable paradox in cancer treatment.
    Farnaz Ahmadi-Dehlaghi, Parisa Mohammadi, Elahe Valipour, Pouya Pournaghi, Sarah Kiani, Kamran Mansouri.
      OBJECTIVE: Autophagy is an intracellular degradation pathway conserved in all eukaryotes from yeast to humans. This process plays a quality-control role by destroying harmful cellular components under normal conditions, maintaining cell survival, and establishing cellular adaptation under stressful conditions. Hence, there are various studies indicating dysfunctional autophagy as a factor involved in the development and progression of various human diseases, including cancer. In addition, the importance of autophagy in the development of cancer has been highlighted by paradoxical roles, as a cytoprotective and cytotoxic mechanism. Despite extensive research in the field of cancer, there are many questions and challenges about the roles and effects suggested for autophagy in cancer treatment. The aim of this study was to provide an overview of the paradoxical roles of autophagy in different tumors and related cancer treatment options.METHODS: In this study, to find articles, a search was made in PubMed and Google scholar databases with the keywords Autophagy, Autophagy in Cancer Management, and Drug Design.
    RESULTS: According to the investigation, some studies suggest that several advanced cancers are dependent on autophagy for cell survival, so when cancer cells are exposed to therapy, autophagy is induced and suppresses the anti-cancer effects of therapeutic agents and also results in cell resistance. However, enhanced autophagy from using anti-cancer drugs causes autophagy-mediated cell death in several cancers. Because autophagy also plays roles in both tumor suppression and promotion further research is needed to determine the precise mechanism of this process in cancer treatment.
    CONCLUSION: We concluded in this article, autophagy manipulation may either promote or hinder the growth and development of cancer according to the origin of the cancer cells, the type of cancer, and the behavior of the cancer cells exposed to treatment. Thus, before starting treatment it is necessary to determine the basal levels of autophagy in various cancers.
    Keywords:  angiogenesis; autophagy; cancer biology; cancer management; drug design; signal transduction
    DOI:  https://doi.org/10.1002/cam4.5577
  5. Nat Cell Biol. 2023 Feb 06.
    Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis.
    Xiaoguang Liu, Litong Nie, Yilei Zhang, Yuelong Yan, Chao Wang, Medina Colic, Kellen Olszewski, Amber Horbath, Xiong Chen, Guang Lei, Chao Mao, Shiqi Wu, Li Zhuang, Masha V Poyurovsky, M James You, Traver Hart, Daniel D Billadeau, Junjie Chen, Boyi Gan.
      SLC7A11-mediated cystine uptake suppresses ferroptosis yet promotes cell death under glucose starvation; the nature of the latter cell death remains unknown. Here we show that aberrant accumulation of intracellular disulfides in SLC7A11high cells under glucose starvation induces a previously uncharacterized form of cell death distinct from apoptosis and ferroptosis. We term this cell death disulfidptosis. Chemical proteomics and cell biological analyses showed that glucose starvation in SLC7A11high cells induces aberrant disulfide bonds in actin cytoskeleton proteins and F-actin collapse in a SLC7A11-dependent manner. CRISPR screens and functional studies revealed that inactivation of the WAVE regulatory complex (which promotes actin polymerization and lamellipodia formation) suppresses disulfidptosis, whereas constitutive activation of Rac promotes disulfidptosis. We further show that glucose transporter inhibitors induce disulfidptosis in SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results reveal that the susceptibility of the actin cytoskeleton to disulfide stress mediates disulfidptosis and suggest a therapeutic strategy to target disulfidptosis in cancer treatment.
    DOI:  https://doi.org/10.1038/s41556-023-01091-2
  6. Commun Biol. 2023 Feb 10. 6(1): 163
    Open-source curation of a pancreatic ductal adenocarcinoma gene expression analysis platform (pdacR) supports a two-subtype model.
    Luke A Torre-Healy, Ryan R Kawalerski, Ki Oh, Lucie Chrastecka, Xianlu L Peng, Andrew J Aguirre, Naim U Rashid, Jen Jen Yeh, Richard A Moffitt.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which potent therapies have limited efficacy. Several studies have described the transcriptomic landscape of PDAC tumors to provide insight into potentially actionable gene expression signatures to improve patient outcomes. Despite centralization efforts from multiple organizations and increased transparency requirements from funding agencies and publishers, analysis of public PDAC data remains difficult. Bioinformatic pitfalls litter public transcriptomic data, such as subtle inclusion of low-purity and non-adenocarcinoma cases. These pitfalls can introduce non-specificity to gene signatures without appropriate data curation, which can negatively impact findings. To reduce barriers to analysis, we have created pdacR ( http://pdacR.bmi.stonybrook.edu , github.com/rmoffitt/pdacR), an open-source software package and web-tool with annotated datasets from landmark studies and an interface for user-friendly analysis in clustering, differential expression, survival, and dimensionality reduction. Using this tool, we present a multi-dataset analysis of PDAC transcriptomics that confirms the basal-like/classical model over alternatives.
    DOI:  https://doi.org/10.1038/s42003-023-04461-6
  7. Clin Cancer Res. 2023 Feb 07. pii: CCR-22-1630. [Epub ahead of print]
    Addition of losartan to FOLFIRINOX and chemoradiation reduces immunosuppression-associated genes, Tregs and FOXP3+ cancer cells in locally advanced pancreatic cancer.
    Yves Boucher, Jessica M Posada, Sonu Subudhi, Ashwin S Kumar, Spencer R Rosario, Liqun Gu, Heena Kumra, Mari Mino-Kenudson, Nilesh P Talele, Dan G Duda, Dai Fukumura, Jennifer Y Wo, Jeffrey W Clark, David P Ryan, Carlos Fernandez-Del Castillo, Theodore S Hong, Mikael J Pittet, Rakesh K Jain.
      PURPOSE: Adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant losartan on the tumor microenvironment.EXPERIMENTAL DESIGN: We performed a gene expression and immunofluorescence (IF) analysis using archived surgical samples from patients treated with LOS+FFX+CRT (NCT01821729), FFX+CRT (NCT01591733) or surgery upfront, without any neoadjuvant therapy. We also conducted a longitudinal analysis of multiple biomarkers in the plasma of treated patients.
    RESULTS: In comparison to FFX+CRT, LOS+FFX+CRT downregulated immunosuppression and pro-invasion genes. Overall survival (OS) was associated with dendritic cell (DC) and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC- and blood vessel-related genes for those treated with LOS+FFX+CRT. Furthermore, losartan induced specific changes in circulating levels of IL-8, sTie2 and TGF-b. IF revealed significantly less residual disease in lesions treated with LOS+FFX+CRT. Lastly, patients with a complete/near complete pathological response in the LOS+FFX+CRT-treated group had reduced CD4+FOXP3+ regulatory T cells (Tregs), fewer immunosuppressive FOXP3+ cancer cells (C-FOXP3) and increased CD8+ T cells in PDAC lesions.
    CONCLUSIONS: Adding losartan to FFX+CRT reduced pro-invasion and immunosuppression related genes which were associated with improved OS in patients with LAPC. Lesions from responders in the LOS+FFX+CRT-treated group had reduced Tregs, decreased C-FOXP3 and increased CD8+ T cells. These findings suggest that losartan may potentiate the benefit of FFX+CRT by reducing immunosuppression.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1630
  8. Elife. 2023 Feb 06. pii: e80809. [Epub ahead of print]12
    Bilateral JNK activation is a hallmark of interface surveillance and promotes elimination of aberrant cells.
    Deepti Prasad, Katharina Illek, Friedericke Fischer, Katrin Holstein, Anne-Kathrin Classen.
      Tissue-intrinsic defense mechanisms eliminate aberrant cells from epithelia and thereby maintain the health of developing tissues or adult organisms. 'Interface surveillance' comprises one such distinct mechanism that specifically guards against aberrant cells which undergo inappropriate cell fate and differentiation programs. The cellular mechanisms which facilitate detection and elimination of these aberrant cells are currently unknown. We find that in Drosophila imaginal discs, clones of cells with inappropriate activation of cell fate programs induce bilateral JNK activation at clonal interfaces, where wild type and aberrant cells make contact. JNK activation is required to drive apoptotic elimination of interface cells. Importantly, JNK activity and apoptosis are highest in interface cells within small aberrant clones, which likely supports the successful elimination of aberrant cells when they arise. Our findings are consistent with a model where clone size affects the topology of interface contacts and thereby the strength of JNK activation in wild type and aberrant interface cells. Bilateral JNK activation is unique to 'interface surveillance' and is not observed in other tissue-intrinsic defense mechanisms, such as classical 'cell-cell competition'. Thus, bilateral JNK interface signaling provides an independent tissue-level mechanism to eliminate cells with inappropriate developmental fate but normal cellular fitness. Finally, oncogenic Ras-expressing clones activate 'interface surveillance' but evade elimination by bilateral JNK activation. Combined, our work establishes bilateral JNK interface signaling and interface apoptosis as a new hallmark of interface surveillance and highlights how oncogenic mutations evade tumor suppressor function encoded by this tissue-intrinsic surveillance system.
    Keywords:  D. melanogaster; JNK; apoptosis; cancer biology; cell competition; cell elimination; developmental biology; epithelial cells; interface contractility
    DOI:  https://doi.org/10.7554/eLife.80809
  9. Nature. 2023 Feb 08.
    Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.
    Joe Nassour, Lucia Gutierrez Aguiar, Adriana Correia, Tobias T Schmidt, Laura Mainz, Sara Przetocka, Candy Haggblom, Nimesha Tadepalle, April Williams, Maxim N Shokhirev, Semih C Akincilar, Vinay Tergaonkar, Gerald S Shadel, Jan Karlseder.
      Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations1,2. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS-STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.
    DOI:  https://doi.org/10.1038/s41586-023-05710-8
  10. Nat Metab. 2023 Feb 06.
    Allosteric regulation of CAD modulates de novo pyrimidine synthesis during the cell cycle.
    Jong Shin, Hannan Mir, Maaz A Khurram, Kenji M Fujihara, Brian D Dynlacht, Timothy J Cardozo, Richard Possemato.
      Metabolism is a fundamental cellular process that is coordinated with cell cycle progression. Despite this association, a mechanistic understanding of cell cycle phase-dependent metabolic pathway regulation remains elusive. Here we report the mechanism by which human de novo pyrimidine biosynthesis is allosterically regulated during the cell cycle. Combining traditional synchronization methods and metabolomics, we characterize metabolites by their accumulation pattern during cell cycle phases and identify cell cycle phase-dependent regulation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase (CAD), the first, rate-limiting enzyme in de novo pyrimidine biosynthesis. Through systematic mutational scanning and structural modelling, we find allostery as a major regulatory mechanism that controls the activity change of CAD during the cell cycle. Specifically, we report evidence of two Animalia-specific loops in the CAD allosteric domain that involve sensing and binding of uridine 5'-triphosphate, a CAD allosteric inhibitor. Based on homology with a mitochondrial carbamoyl-phosphate synthetase homologue, we identify a critical role for a signal transmission loop in regulating the formation of a substrate channel, thereby controlling CAD activity.
    DOI:  https://doi.org/10.1038/s42255-023-00735-9
  11. Cell Death Discov. 2023 Feb 06. 9(1): 45
    Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms.
    Benoît Marchand, Marc-Antoine Poulin, Christine Lawson, Lee-Hwa Tai, Steve Jean, Marie-Josée Boucher.
      Gemcitabine is a first-line treatment agent for pancreatic ductal adenocarcinoma (PDAC). Contributing to its cytotoxicity, this chemotherapeutic agent is primarily a DNA replication inhibitor that also induces DNA damage. However, its therapeutic effects are limited owing to chemoresistance. Evidence in the literature points to a role for autophagy in restricting the efficacy of gemcitabine. Autophagy is a catabolic process in which intracellular components are delivered to degradative organelles lysosomes. Interfering with this process sensitizes PDAC cells to gemcitabine. It is consequently inferred that autophagy and lysosomal function need to be tightly regulated to maintain homeostasis and provide resistance to environmental stress, such as those imposed by chemotherapeutic drugs. However, the mechanism(s) through which gemcitabine promotes autophagy remains elusive, and the impact of gemcitabine on lysosomal function remains largely unexplored. Therefore, we applied complementary approaches to define the mechanisms triggered by gemcitabine that support autophagy and lysosome function. We found that gemcitabine elicited ERK-dependent autophagy in PDAC cells, but did not stimulate ERK activity or autophagy in non-tumoral human pancreatic epithelial cells. Gemcitabine also promoted transcription factor EB (TFEB)-dependent lysosomal function in PDAC cells. Indeed, treating PDAC cells with gemcitabine caused expansion of the lysosomal network, as revealed by Lysosome associated membrane protein-1 (LAMP1) and LysoTracker staining. More specific approaches have shown that gemcitabine promotes the activity of cathepsin B (CTSB), a cysteine protease playing an active role in lysosomal degradation. We showed that lysosomal function induced by gemcitabine depends on TFEB, the master regulator of autophagy and lysosomal biogenesis. Interfering with TFEB function considerably limited the clonogenic growth of PDAC cells and hindered the capacity of TFEB-depleted PDAC cells to develop orthotopic tumors.
    DOI:  https://doi.org/10.1038/s41420-023-01342-z
  12. Nat Rev Drug Discov. 2023 Feb 09.
    Targeting galectin-driven regulatory circuits in cancer and fibrosis.
    Karina V Mariño, Alejandro J Cagnoni, Diego O Croci, Gabriel A Rabinovich.
      Galectins are a family of endogenous glycan-binding proteins that have crucial roles in a broad range of physiological and pathological processes. As a group, these proteins use both extracellular and intracellular mechanisms as well as glycan-dependent and independent pathways to reprogramme the fate and function of numerous cell types. Given their multifunctional roles in both tissue fibrosis and cancer, galectins have been identified as potential therapeutic targets for these disorders. Here, we focus on the therapeutic relevance of galectins, particularly galectin 1 (GAL1), GAL3 and GAL9 to tumour progression and fibrotic diseases. We consider an array of galectin-targeted strategies, including small-molecule carbohydrate inhibitors, natural polysaccharides and their derivatives, peptides, peptidomimetics and biological agents (notably, neutralizing monoclonal antibodies and truncated galectins) and discuss their mechanisms of action, selectivity and therapeutic potential in preclinical models of fibrosis and cancer. We also review the results of clinical trials that aim to evaluate the efficacy of galectin inhibitors in patients with idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis and cancer. The rapid pace of glycobiology research, combined with the acute need for drugs to alleviate fibrotic inflammation and overcome resistance to anticancer therapies, will accelerate the translation of anti-galectin therapeutics into clinical practice.
    DOI:  https://doi.org/10.1038/s41573-023-00636-2
  13. J Cell Biol. 2023 Apr 03. pii: e202109090. [Epub ahead of print]222(4):
    Human atlastins are sufficient to drive the fusion of liposomes with a physiological lipid composition.
    Eunhong Jang, Yeojin Moon, So Young Yoon, Joyce Anne R Diaz, Miriam Lee, Naho Ko, Jongseo Park, Soo Hyun Eom, Changwook Lee, Youngsoo Jun.
      The dynamin-like GTPase atlastin is believed to be the minimal machinery required for homotypic endoplasmic reticulum (ER) membrane fusion, mainly because Drosophila atlastin is sufficient to drive liposome fusion. However, it remains unclear whether mammalian atlastins, including the three human atlastins, are sufficient to induce liposome fusion, raising doubts about their major roles in mammalian cells. Here, we show that all human atlastins are sufficient to induce fusion when reconstituted into liposomes with a lipid composition mimicking that of the ER. Although the fusogenic activity of ATL1, which is predominantly expressed in neuronal cells, was weaker than that of ATL2 or ATL3, the addition of M1-spastin, a neuron-specific factor, markedly increased ATL1-mediated liposome fusion. Although we observed efficient fusion between ER microsomes isolated from cultured, non-neuronal cells that predominantly express ATL2-1, an autoinhibited isoform of ATL2, ATL2-1 failed to support liposome fusion by itself as reported previously, indicating that cellular factors enable ATL2-1 to mediate ER fusion in vivo.
    DOI:  https://doi.org/10.1083/jcb.202109090
  14. Ann Surg. 2023 Feb 01. 277(2): e396-e405
    The Impact of Molecular Subtyping on Pathological Staging of Pancreatic Cancer.
    Australian Pancreatic Cancer Genome Initiative
      BACKGROUND: The long-term outcomes following surgical resection for pancreatic ductal adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains suboptimal largely due to the absence of consideration of aggressive tumor biology.OBJECTIVE: The aim of this study was to evaluate traditional staging criteria for PDAC in the setting of molecular subtypes.
    METHODS: Clinicopathological data were obtained for 5 independent cohorts of consecutive unselected patients, totaling n = 1298, including n = 442 that underwent molecular subtyping. The main outcome measure was disease-specific survival following surgical resection for PDAC stratified according to the American Joint Commission for Cancer (TNM) staging criteria, margin status, and molecular subtype.
    RESULTS: TNM staging criteria and margin status confers prognostic value only in tumors with classical pancreatic subtype. Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, P = 0.032]. Margin status has no impact on survival in the squamous subtype (16.0 vs 12.1 months, P = 0.374). There were no differences in molecular subtype or gene expression of tumors with positive resection margin status.
    CONCLUSIONS: Aggressive tumor biology as measured by molecular subtype predicts poor outcome following pancreatectomy for PDAC and should be utilized to inform patient selection for surgery.
    DOI:  https://doi.org/10.1097/SLA.0000000000005050
  15. JCI Insight. 2023 Feb 08. pii: e152714. [Epub ahead of print]8(3):
    Developing SHP2-based combination therapy for KRAS-amplified cancer.
    Tianxia Li, Osamu Kikuchi, Jin Zhou, Yichen Wang, Babita Pokharel, Klavdija Bastl, Prafulla Gokhale, Aine Knott, Yanxi Zhang, John G Doench, Zandra V Ho, Daniel Vt Catenacci, Adam J Bass.
      Gastroesophageal adenocarcinomas (GEAs) harbor recurrent amplification of KRAS, leading to marked overexpression of WT KRAS protein. We previously demonstrated that SHP2 phosphatase, which acts to promote KRAS and downstream MAPK pathway activation, is a target in these tumors when combined with MEK inhibition. We hypothesized that SHP2 inhibitors may serve as a foundation for developing novel combination inhibitor strategies for therapy of KRAS-amplified GEA, including with targets outside the MAPK pathway. Here, we explore potential targets to effectively augment the efficacy of SHP2 inhibition, starting with genome-wide CRISPR screens in KRAS-amplified GEA cell lines with and without SHP2 inhibition. We identify candidate targets within the MAPK pathway and among upstream RTKs that may enhance SHP2 efficacy in KRAS-amplified GEA. Additional in vitro and in vivo experiments demonstrated the potent cytotoxicity of pan-ERBB kinase inhibitions in vitro and in vivo. Furthermore, beyond targets within the MAPK pathway, we demonstrate that inhibition of CDK4/6 combines potently with SHP2 inhibition in KRAS-amplified GEA, with greater efficacy of this combination in KRAS-amplified, compared with KRAS-mutant, tumors. These results suggest therapeutic combinations for clinical study in KRAS-amplified GEAs.
    Keywords:  Drug therapy; Oncogenes; Oncology; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.152714
  16. Trends Cancer. 2023 Feb 07. pii: S2405-8033(23)00006-7. [Epub ahead of print]
    Preclinical models to study patient-derived circulating tumor cells and metastasis.
    Kanve N Suvilesh, Yariswamy Manjunath, Klaus Pantel, Jussuf T Kaifi.
      Circulating tumor cells (CTCs) that are detached from the tumor can be precursors of metastasis. The majority of studies focus on enumeration of CTCs from patient blood to predict recurrence and therapy outcomes. Very few studies have managed to expand CTCs to investigate their functional dynamics with respect to genetic changes, tumorigenic potential, and response to drug treatment. A growing amount of evidence based on successful CTC expansion has revealed novel therapeutic targets that are associated with the process of metastasis. In this review, we summarize the successes, challenges, and limitations that collectively contribute to the better understanding of metastasis using patient-derived CTCs as blood-borne seeds of metastasis. The roadblocks and future avenues to move CTC-based scientific discoveries forward are also discussed.
    Keywords:  circulating tumor cells; humanized mouse models of cancer; metastasis; patient-derived xenografts; preclinical models
    DOI:  https://doi.org/10.1016/j.trecan.2023.01.004
  17. Cancer Metastasis Rev. 2023 Feb 09.
    Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution.
    Federica Francescangeli, Maria Laura De Angelis, Rachele Rossi, Adriano Cuccu, Alessandro Giuliani, Ruggero De Maria, Ann Zeuner.
      The biological complexity of cancer represents a tremendous clinical challenge, resulting in the frequent failure of current treatment protocols. In the rapidly evolving scenario of a growing tumor, anticancer treatments impose a drastic perturbation not only to cancer cells but also to the tumor microenvironment, killing a portion of the cells and inducing a massive stress response in the survivors. Consequently, treatments can act as a double-edged sword by inducing a temporary response while laying the ground for therapy resistance and subsequent disease progression. Cancer cell dormancy (or quiescence) is a central theme in tumor evolution, being tightly linked to the tumor's ability to survive cytotoxic challenges, metastasize, and resist immune-mediated attack. Accordingly, quiescent cancer cells (QCCs) have been detected in virtually all the stages of tumor development. In recent years, an increasing number of studies have focused on the characterization of quiescent/therapy resistant cancer cells, unveiling QCCs core transcriptional programs, metabolic plasticity, and mechanisms of immune escape. At the same time, our partial understanding of tumor quiescence reflects the difficulty to identify stable QCCs biomarkers/therapeutic targets and to control cancer dormancy in clinical settings. This review focuses on recent discoveries in the interrelated fields of dormancy, stemness, and therapy resistance, discussing experimental evidences in the frame of a nonlinear dynamics approach, and exploring the possibility that tumor quiescence may represent not only a peril but also a potential therapeutic resource.
    Keywords:  Cancer stem cells; Dormancy; Quiescence; Stemness; Therapy resistance; Tumor relapse
    DOI:  https://doi.org/10.1007/s10555-023-10092-4
  18. Cancer Discov. 2023 Feb 06. OF1-OF30
    Discovery of Targets for Immune-Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha.
    Avinash Sahu, Xiaoman Wang, Phillip Munson, Jan P G Klomp, Xiaoqing Wang, Shengqing Stan Gu, Ya Han, Gege Qian, Phillip Nicol, Zexian Zeng, Chenfei Wang, Collin Tokheim, Wubing Zhang, Jingxin Fu, Jin Wang, Nishanth Ulhas Nair, Joost A P Rens, Meriem Bourajjaj, Bas Jansen, Inge Leenders, Jaap Lemmers, Mark Musters, Sanne van Zanten, Laura van Zelst, Jenny Worthington, Jun S Liu, Dejan Juric, Clifford A Meyer, Arthur Oubrie, X Shirley Liu, David E Fisher, Keith T Flaherty.
      Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway and then used it to identify 38 candidate immune-metabolic regulators. We show the tumor activities of these regulators stratify patients with melanoma by their response to anti-PD-1 using machine learning and deep neural approaches, which improve the predictive power of current biomarkers. The topmost identified regulator, ESRRA, is activated in immunotherapy-resistant tumors. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization, and (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth suppressor evasion pathways. BipotentR (http://bipotentr.dfci.harvard.edu/) provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms.SIGNIFICANCE: BipotentR presents resources for evaluating patient response and identifying targets for drugs that can kill tumors through multiple mechanisms concurrently. Inhibition of the topmost candidate target killed tumors by suppressing energy metabolism and effects on two immune mechanisms.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0244
  19. Anal Chem. 2023 Feb 09.
    mNeuCode Empowers Targeted Proteome Analysis of Arginine Dimethylation.
    Qianqian Wang, Xin Yan, Bin Fu, Ying Xu, Lingjun Li, Cheng Chang, Chenxi Jia.
      Characterization of protein arginine dimethylation presents significant challenges due to its occurrence at the substoichiometric level. To enable a targeted MS/MS analysis of these dimethylation sites, we developed the mNeuCode (methyl-neutron-coding) tag by metabolically labeling methylarginine with stable isotopes during cell culture, which generated a diagnostic peak containing the NeuCode isotopologue signature in a high-resolution MS scan. A software tool, termed NeuCodeFinder, was developed for screening the NeuCode signatures in mass spectra. Therefore, a targeted MS/MS workflow was established for proteome-wide discovery of arginine dimethylation. The efficacy and utility were demonstrated by identifying 176 arginine dimethylation sites residing on 70 proteins in HeLa cells. Among them, 38% of the sites and 29% of the dimethylated proteins are novel, including five novel arginine dimethylation sites on the protein FAM98A, which is a substrate of protein arginine methyltransferase 1 (PRMT1). Our results show that deletion of FAM98A in HeLa cells suppressed cell migration, and importantly, dimethylation-deficient mutation suppressed this process as well. Therefore, the PRMT1-FAM98A pathway mediates cell migration possibly through dimethylation of these newly identified sites of FAM98A. Our study might drive the methodological shift from shotgun-based to targeted proteome analysis for interrogation of the substoichiometric biomolecules by using NeuCode-enabled techniques.
    DOI:  https://doi.org/10.1021/acs.analchem.2c04648
  20. Autophagy. 2023 Feb 05. 1-15
    G-quadruplex ligands as potent regulators of lysosomes.
    Lucille Ferret, Karla Alvarez-Valadez, Jennifer Rivière, Alexandra Muller, Natalia Bohálová, Luo Yu, Lionel Guittat, Vaclav Brázda, Guido Kroemer, Jean-Louis Mergny, Mojgan Djavaheri-Mergny.
      Guanine-quadruplex structures (G4) are unusual nucleic acid conformations formed by guanine-rich DNA and RNA sequences and known to control gene expression mechanisms, from transcription to protein synthesis. So far, a number of molecules that recognize G4 have been developed for potential therapeutic applications in human pathologies, including cancer and infectious diseases. These molecules are called G4 ligands. When the biological effects of G4 ligands are studied, the analysis is often limited to nucleic acid targets. However, recent evidence indicates that G4 ligands may target other cellular components and compartments such as lysosomes and mitochondria. Here, we summarize our current knowledge of the regulation of lysosome by G4 ligands, underlying their potential functional impact on lysosome biology and autophagic flux, as well as on the transcriptional regulation of lysosomal genes. We outline the consequences of these effects on cell fate decisions and we systematically analyzed G4-prone sequences within the promoter of 435 lysosome-related genes. Finally, we propose some hypotheses about the mechanisms involved in the regulation of lysosomes by G4 ligands.
    Keywords:  Autophagy; TFEB; guanine-quadruplex; lysosome membrane permeabilization; transcriptional regulation
    DOI:  https://doi.org/10.1080/15548627.2023.2170071
  21. Genome Med. 2023 Feb 09. 15(1): 8
    Pervasiveness of HLA allele-specific expression loss across tumor types.
    Ioan Filip, Anqi Wang, Oleksandr Kravets, Rose Orenbuch, Junfei Zhao, Tomin E Perea-Chamblee, Gulam A Manji, Evangelina López de Maturana, Núria Malats, Kenneth P Olive, Raul Rabadan.
      BACKGROUND: Efficient presentation of mutant peptide fragments by the human leukocyte antigen class I (HLA-I) genes is necessary for immune-mediated killing of cancer cells. According to recent reports, patient HLA-I genotypes can impact the efficacy of cancer immunotherapy, and the somatic loss of HLA-I heterozygosity has been established as a factor in immune evasion. While global deregulated expression of HLA-I has also been reported in different tumor types, the role of HLA-I allele-specific expression loss - that is, the preferential RNA expression loss of specific HLA-I alleles - has not been fully characterized in cancer.METHODS: Here, we use RNA and whole-exome sequencing data to quantify HLA-I allele-specific expression (ASE) in cancer using our novel method arcasHLA-quant.
    RESULTS: We show that HLA-I ASE loss in at least one of the three HLA-I genes is a pervasive phenomenon across TCGA tumor types. In pancreatic adenocarcinoma, tumor-specific HLA-I ASE loss is associated with decreased overall survival specifically in the basal-like subtype, a finding that we validated in an independent cohort through laser-capture microdissection. Additionally, we show that HLA-I ASE loss is associated with poor immunotherapy outcomes in metastatic melanoma through retrospective analyses.
    CONCLUSIONS: Together, our results highlight the prevalence of HLA-I ASE loss and provide initial evidence of its clinical significance in cancer prognosis and immunotherapy treatment.
    Keywords:  Allele-specific expression; HLA; Immunotherapy; Loss of heterogeneity; Pan-cancer analysis; Pancreatic cancer
    DOI:  https://doi.org/10.1186/s13073-023-01154-x
  22. Nat Commun. 2023 Feb 09. 14(1): 709
    Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo.
    Konxhe Kulaj, Alexandra Harger, Michaela Bauer, Özüm S Caliskan, Tilak Kumar Gupta, Dapi Menglin Chiang, Edward Milbank, Josefine Reber, Angelos Karlas, Petra Kotzbeck, David N Sailer, Francesco Volta, Dominik Lutter, Sneha Prakash, Juliane Merl-Pham, Vasilis Ntziachristos, Hans Hauner, Michael W Pfaffl, Matthias H Tschöp, Timo D Müller, Stefanie M Hauck, Benjamin D Engel, Jantje M Gerdes, Paul T Pfluger, Natalie Krahmer, Kerstin Stemmer.
      Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand.
    DOI:  https://doi.org/10.1038/s41467-023-36148-1
  23. Cancers (Basel). 2023 Feb 03. pii: 970. [Epub ahead of print]15(3):
    Utility of Comprehensive Genomic Profiling Tests for Patients with Incurable Pancreatic Cancer in Clinical Practice.
    Takuo Yamai, Kenji Ikezawa, Naotoshi Sugimoto, Makiko Urabe, Yugo Kai, Ryoji Takada, Tasuku Nakabori, Hiroyuki Uehara, Takahisa Kawamura, Kei Kunimasa, Sachiko Yamamoto, Toru Wakamatsu, Takuji Hayashi, Yoji Kukita, Fumie Fujisawa, Tazuko Inoue, Yuko Yamaguchi, Tomoyuki Yamasaki, Keiichiro Honma, Kazuyoshi Ohkawa.
      Although comprehensive genomic profiling (CGP) tests have been covered under the Japanese national health insurance program since 2018, the utility and issues of CGP tests have not been clarified. We retrospectively reviewed 115 patients with incurable pancreatic cancer (IPC) who underwent CGP tests in a Japanese cancer referral center from November 2019 to August 2021. We evaluated the results of CGP tests, treatments based on CGP tests, and survival time. Eight cases (6.9%) were diagnosed as tumor mutation burden-high (TMB-H) and/or microsatellite instability-high (MSI-H). The gene mutation rates of KRAS/TP53/CDKN2A/SMAD4 were 93.0/83.0/53.0/25.2%, respectively. Twenty-five patients (21.7%) had homologous recombination deficiency (HRD)-related genetic mutations. Four patients (3.5%) having TMB-H and/or MSI-H were treated with pembrolizumab, and only two patients (1.7%) participated in the clinical trials. Patient characteristics were not significantly different between patients with and without HRD-related gene mutations. The median OS was significantly longer in the HRD (+) group than in the HRD (-) group (749 days vs. 519 days, p = 0.047). In multivariate analysis, HRD-related gene mutation was an independent prognostic factor associated with favorable OS. CGP tests for patients with IPC have the potential utility of detecting HRD-related gene mutations as prognostic factors as well as a therapeutic search.
    Keywords:  comprehensive genomic profiling tests; homologous recombination deficiency; pancreatic cancer
    DOI:  https://doi.org/10.3390/cancers15030970
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