bims-cagime 2021-09-12 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2021–09–12
27 papers selected by
Kıvanç Görgülü, Technical University of Munich

The expanding role of Atg8.
Models of pancreatic ductal adenocarcinoma.
Targeting KRAS in pancreatic cancer: new drugs on the horizon.
Three dimensions of autophagy in regulating tumor growth: Cell survival/death, cell proliferation, and tumor dormancy.
MRI-Determined Psoas Muscle Fat Infiltration Correlates with Severity of Weight Loss during Cancer Cachexia.
Using DNA sequencing data to quantify T cell fraction and therapy response.
A Perspective on the Role of Autophagy in Cancer.
Macroautophagy and aging: The impact of cellular recycling on health and longevity.
Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression.
Proteasome and selective autophagy: Brothers-in-arms for organelle quality control.
Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis.
Targeting DNA Damage Repair Mechanisms in Pancreas Cancer.
Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.
Low and high pancreatic amylase is associated with pancreatic cancer and chronic pancreatitis.
Cells of the human intestinal tract mapped across space and time.
Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines.
Proteogenomic analysis of pancreatic cancer subtypes.
Clinical and therapeutic relevance of cancer-associated fibroblasts.
Autophagic flux in cancer cells at the invasive front in the tumor-stroma border.
Chronic stress primes innate immune responses in mice and humans.
Stress and cancer: mechanisms, significance and future directions.
DNA methylation and histone variants in aging and cancer.
p62 condensates are a hub for proteasome-mediated protein turnover in the nucleus.
Protein-gene Expression Nexus: Comprehensive characterization of human cancer cell lines with proteogenomic analysis.
Autophagy in metabolic disease and ageing.
Glutamine promotes escape from therapy-induced senescence in tumor cells.
Identification of Key mRNAs as Prediction Models for Early Metastasis of Pancreatic Cancer Based on LASSO.

Autophagy. 2021 Sep 05. 1-2

The expanding role of Atg8.

Wayne D Hawkins, Daniel J Klionsky.

  It would be quite convenient if every protein had one distinct function, one distinct role in just a single cellular process. In the field of macroautophagy/autophagy, however, we are increasingly finding that this is not the case; several autophagy proteins have two or more roles within the process of autophagy and many even "moonlight" as functional members of entirely different cellular processes. This is perhaps best exemplified by the Atg8-family proteins. These dynamic proteins have already been reported to serve several functions both within autophagy (membrane tethering, membrane fusion, binding to cargo receptors, binding to autophagy machinery) and beyond (LC3-associated phagocytosis, formation of EDEMosomes, immune signaling) but as Maruyama and colleagues suggest in their recent report, this list of functions may not yet be complete.

Keywords:  Autophagosome; autophagy; lipidation; membrane expansion; phagophore

DOI:  https://doi.org/10.1080/15548627.2021.1967566
Cancer Metastasis Rev. 2021 Sep 07.

Models of pancreatic ductal adenocarcinoma.

Rayane Dennaoui, Hridaya Shrestha, Kay-Uwe Wagner.

  Although pancreatic cancer remains to be a leading cause of cancer-related deaths in many industrialized countries, there have been major advances in research over the past two decades that provided a detailed insight into the molecular and developmental processes that govern the genesis of this highly malignant tumor type. There is a continuous need for the development and analysis of preclinical and genetically engineered pancreatic cancer models to study the biological significance of new molecular targets that are identified using various genome-wide approaches and to better understand the mechanisms by which they contribute to pancreatic cancer onset and progression. Following an introduction into the etiology of pancreatic cancer, the molecular subtypes, and key signaling pathways, this review provides an overview of the broad spectrum of models for pancreatic cancer research. In addition to conventional and patient-derived xenografting, this review highlights major milestones in the development of chemical carcinogen-induced and genetically engineered animal models to study pancreatic cancer. Particular emphasis was placed on selected research findings of ligand-controlled tumor models and current efforts to develop genetically engineered strains to gain insight into the biological functions of genes at defined developmental stages during cancer initiation and metastatic progression.

Keywords:  Adenocarcinoma; Dormancy; KRAS; MYC; Metastasis; Pancreatic cancer

DOI:  https://doi.org/10.1007/s10555-021-09989-9
Cancer Metastasis Rev. 2021 Sep 09.

Targeting KRAS in pancreatic cancer: new drugs on the horizon.

Sahar F Bannoura, Md Hafiz Uddin, Misako Nagasaka, Farzeen Fazili, Mohammed Najeeb Al-Hallak, Philip A Philip, Bassel El-Rayes, Asfar S Azmi.

  Kirsten Rat Sarcoma (KRAS) is a master oncogene involved in cellular proliferation and survival and is the most commonly mutated oncogene in all cancers. Activating KRAS mutations are present in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases and are implicated in tumor initiation and progression. Although KRAS is a critical oncogene, and therefore an important therapeutic target, its therapeutic inhibition has been very challenging, and only recently specific mutant KRAS inhibitors have been discovered. In this review, we discuss the activation of KRAS signaling and the role of mutant KRAS in PDAC development. KRAS has long been considered undruggable, and many drug discovery efforts which focused on indirect targeting have been unsuccessful. We discuss the various efforts for therapeutic targeting of KRAS. Further, we explore the reasons behind these obstacles, novel successful approaches to target mutant KRAS including G12C mutation as well as the mechanisms of resistance.

Keywords:  KRAS; KRAS inhibitor; KRAS vaccine; KRASG12C; KRASG12C inhibitors; PROTACs; Pancreatic cancer

DOI:  https://doi.org/10.1007/s10555-021-09990-2
Biochim Biophys Acta Mol Basis Dis. 2021 Sep 03. pii: S0925-4439(21)00198-8. [Epub ahead of print] 166265

Three dimensions of autophagy in regulating tumor growth: Cell survival/death, cell proliferation, and tumor dormancy.

Yongqiang Chen, Spencer B Gibson.

  Autophagy is an intracellular lysosomal degradation process involved in multiple facets of cancer biology. Various dimensions of autophagy are associated with tumor growth and cancer progression, and here we focus on the dimensions involved in regulation of cell survival/cell death, cell proliferation and tumor dormancy. The first dimension of autophagy supports cell survival under stress within tumors and under certain contexts drives cell death, impacting tumor growth. The second dimension of autophagy promotes proliferation through directly regulating cell cycle or indirectly maintaining metabolism, increasing tumor growth. The third dimension of autophagy facilitates tumor cell dormancy, contributing to cancer treatment resistance and cancer recurrence. The intricate relationship between these three dimensions of autophagy influences the extent of tumor growth and cancer progression. In this review, we summarize the roles of the three dimensions of autophagy in tumor growth and cancer progression, and discuss unanswered questions in these fields.

Keywords:  Autophagy; Cell death; Cell survival; Proliferation; Tumor dormacy; Tumor growth

DOI:  https://doi.org/10.1016/j.bbadis.2021.166265
Cancers (Basel). 2021 Sep 02. pii: 4433. [Epub ahead of print]13(17):

MRI-Determined Psoas Muscle Fat Infiltration Correlates with Severity of Weight Loss during Cancer Cachexia.

Lisa Patzelt, Daniela Junker, Jan Syväri, Egon Burian, Mingming Wu, Olga Prokopchuk, Ulrich Nitsche, Marcus R Makowski, Rickmer F Braren, Stephan Herzig, Mauricio Berriel Diaz, Dimitrios C Karampinos.

   PURPOSE: To evaluate the suitability of psoas and erector spinae muscle proton density fat fraction (PDFF) and fat volume as biomarkers for monitoring cachexia severity in an oncological cohort, and to evaluate regional variances in muscle parameters over time.
METHODS: In this prospective study, 58 oncological patients were examined by a 3 T MRI receiving between one and five scans. Muscle volume and PDFF were measured, segmentation masks were divided into proximal, middle and distal muscle section.
RESULTS: A regional variation of fat distribution in erector spinae muscle at baseline was found (p < 0.01). During follow-ups significant relative change of muscle parameters was observed. Relative maximum change of erector spinae muscle showed a significant regional variation. Correlation testing with age as a covariate revealed significant correlations for baseline psoas fat volume (r = -0.55, p < 0.01) and baseline psoas PDFF (r = -0.52, p = 0.02) with maximum BMI change during the course of the disease.
CONCLUSION: In erector spinae muscles, a regional variation of fat distribution at baseline and relative maximum change of muscle parameters was observed. Our results indicate that psoas muscle PDFF and fat volume could serve as MRI-determined biomarkers for early risk stratification and disease monitoring regarding progression and severity of weight loss in cancer cachexia.

Keywords:  cancer cachexia; magnetic resonance imaging; proton density fat fraction (PDFF); skeletal muscle; weight loss

DOI:  https://doi.org/10.3390/cancers13174433
Nature. 2021 Sep 08.

Using DNA sequencing data to quantify T cell fraction and therapy response.

TRACERx Consortium

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes.

DOI: https://doi.org/10.1038/s41586-021-03894-5
Biochim Biophys Acta Mol Basis Dis. 2021 Sep 01. pii: S0925-4439(21)00195-2. [Epub ahead of print] 166262

A Perspective on the Role of Autophagy in Cancer.

Aileen R Ariosa, Vikramjit Lahiri, Yuchen Lei, Ying Yang, Zhangyuan Yin, Zhihai Zhang, Daniel J Klionsky.

  Autophagy refers to a ubiquitous set of catabolic pathways required to achieve proper cellular homeostasis. Aberrant autophagy has been implicated in a multitude of diseases including cancer. In this review, we highlight pioneering and groundbreaking research that centers on delineating the role of autophagy in cancer initiation, proliferation and metastasis. First, we discuss the autophagy-related (ATG) proteins and their respective roles in the de novo formation of autophagosomes and the subsequent delivery of cargo to the lysosome for recycling. Next, we touch upon the history of cancer research that centers upon ATG proteins and regulatory mechanisms that control an appropriate autophagic response and how these are altered in the diseased state. Then, we discuss the various discoveries that led to the idea of autophagy as a double-edged sword when it comes to cancer therapy. This review also briefly narrates how different types of autophagy-selective macroautophagy and chaperone-mediated autophagy, have been linked to different cancers. Overall, these studies build upon a steadfast trajectory that aims to solve the monumentally daunting challenge of finding a cure for many types of cancer by modulating autophagy either through inhibition or induction.

Keywords:  Autophagy; cancer; chaperone-mediated autophagy; history; selective autophagy; treatment

DOI:  https://doi.org/10.1016/j.bbadis.2021.166262
Mol Aspects Med. 2021 Sep 07. pii: S0098-2997(21)00080-7. [Epub ahead of print] 101020

Macroautophagy and aging: The impact of cellular recycling on health and longevity.

Jose L Nieto-Torres, Malene Hansen.

  Aging is associated with many deleterious changes at the cellular level, including the accumulation of potentially toxic components that can have devastating effects on health. A key protective mechanism to this end is the cellular recycling process called autophagy. During autophagy, damaged or surplus cellular components are delivered to acidic vesicles called lysosomes, that secure degradation and recycling of the components. Numerous links between autophagy and aging exist. Autophagy declines with age, and increasing evidence suggests that this reduction plays important roles in both physiological aging and the development of age-associated disorders. Studies in pharmacologically and genetically manipulated model organisms indicate that defects in autophagy promote age-related diseases, and conversely, that enhancement of autophagy has beneficial effects on both healthspan and lifespan. Here, we review our current understanding of the role of autophagy in different physiological processes and their molecular links with aging and age-related diseases. We also highlight some recent advances in the field that could accelerate the development of autophagy-based therapeutic interventions.

Keywords:  AMPK; Aging; Autophagy; C. elegans; Healthspan; Lifespan; Neurodegeneration; mTOR

DOI:  https://doi.org/10.1016/j.mam.2021.101020
Cancers (Basel). 2021 Sep 04. pii: 4457. [Epub ahead of print]13(17):

Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression.

Jesusa Capera, Mireia Pérez-Verdaguer, María Navarro-Pérez, Antonio Felipe.

  The voltage-gated potassium channel Kv1.3 is a potential therapeutic target for obesity and diabetes. The genetic ablation and pharmacological inhibition of Kv1.3 lead to a lean phenotype in rodents. The mechanism of regulation of body weight and energy homeostasis involves Kv1.3 expression in different organs, including white and brown adipose tissues. Here, we show that Kv1.3 promotes the proliferation of preadipocytes through the control of mitochondrial dynamics. Kv1.3 is expressed in mitochondria exhibiting high affinity for the perinuclear population. The mitochondrial network is highly dynamic during the cell cycle, showing continuous fusion-fission events. The formation of a hyperfused mitochondrial network at the G1/S phase of the cell cycle is dependent on Kv1.3 expression. Our results demonstrate that Kv1.3 promotes preadipocyte proliferation and differentiation by controlling mitochondrial membrane potential and mitochondrial dynamics at the G1 phase of the cell cycle.

Keywords:  adipocytes; fusion/fission; mitochondria; potassium channels; proliferation

DOI:  https://doi.org/10.3390/cancers13174457
Curr Opin Plant Biol. 2021 Sep 03. pii: S1369-5266(21)00106-0. [Epub ahead of print]63 102106

Proteasome and selective autophagy: Brothers-in-arms for organelle quality control.

Marion Clavel, Yasin Dagdas.

  Maintaining the integrity of organelles despite the cellular disturbances that arise during stress is essential for life. To ensure organelle proteostasis (protein homeostasis), plants have evolved multitiered quality control mechanisms that work together to repair or recycle the damaged organelles. Despite recent advances, our understanding of plant organelle quality control mechanisms is far from complete. Especially, the crosstalk between different quality control pathways remains elusive. Here, we highlight recent advances on organelle quality control, focusing on the targeted protein degradation pathways that maintain the homeostasis of the endoplasmic reticulum (ER), chloroplast, and mitochondria. We discuss how plant cells decide to employ different degradation pathways and propose tools that could be used to discover the missing components in organelle quality control.

Keywords:  CDC48; Model substrates; Organelle quality control; Proteasome; Selective autophagy; Unfolded protein response; Viral replication

DOI:  https://doi.org/10.1016/j.pbi.2021.102106
Nature. 2021 Sep 08.

Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis.

Roarke A Kamber, Yoko Nishiga, Bhek Morton, Allison M Banuelos, Amira A Barkal, Felipe Vences-Catalán, Mingxin Gu, Daniel Fernandez, Jose A Seoane, David Yao, Katherine Liu, Sijie Lin, Kaitlyn Spees, Christina Curtis, Livnat Jerby-Arnon, Irving L Weissman, Julien Sage, Michael C Bassik.

Monoclonal antibody therapies targeting tumour antigens drive cancer cell elimination in large part by triggering macrophage phagocytosis of cancer cells1-7. However, cancer cells evade phagocytosis using mechanisms that are incompletely understood. Here we develop a platform for unbiased identification of factors that impede antibody-dependent cellular phagocytosis (ADCP) using complementary genome-wide CRISPR knockout and overexpression screens in both cancer cells and macrophages. In cancer cells, beyond known factors such as CD47, we identify many regulators of susceptibility to ADCP, including the poorly characterized enzyme adipocyte plasma membrane-associated protein (APMAP). We find that loss of APMAP synergizes with tumour antigen-targeting monoclonal antibodies and/or CD47-blocking monoclonal antibodies to drive markedly increased phagocytosis across a wide range of cancer cell types, including those that are otherwise resistant to ADCP. Additionally, we show that APMAP loss synergizes with several different tumour-targeting monoclonal antibodies to inhibit tumour growth in mice. Using genome-wide counterscreens in macrophages, we find that the G-protein-coupled receptor GPR84 mediates enhanced phagocytosis of APMAP-deficient cancer cells. This work reveals a cancer-intrinsic regulator of susceptibility to antibody-driven phagocytosis and, more broadly, expands our knowledge of the mechanisms governing cancer resistance to macrophage phagocytosis.

DOI: https://doi.org/10.1038/s41586-021-03879-4
Cancers (Basel). 2021 Aug 24. pii: 4259. [Epub ahead of print]13(17):

Targeting DNA Damage Repair Mechanisms in Pancreas Cancer.

Lukas Perkhofer, Talia Golan, Pieter-Jan Cuyle, Tamara Matysiak-Budnik, Jean-Luc Van Laethem, Teresa Macarulla, Estelle Cauchin, Alexander Kleger, Alica K Beutel, Johann Gout, Albrecht Stenzinger, Eric Van Cutsem, Joaquim Bellmunt, Pascal Hammel, Eileen M O'Reilly, Thomas Seufferlein.

  Impaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, BRCA1/2, PALB2, ATM, MSH2, MSH6 and MLH1. Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline BRCA1/2-mutated PDAC. Extending this outcome to the significant proportion of human PDACs with somatic or germline mutations in DDR genes beyond BRCA1/2 might be beneficial, but there is a lack of data, and consequently, no clear recommendations are provided in the field. Therefore, an expert panel was invited by the European Society of Digestive Oncology (ESDO) to assess the current knowledge and significance of DDR as a target in PDAC treatment. The aim of this virtual, international expert meeting was to elaborate a set of consensus recommendations on testing, diagnosis and treatment of PDAC patients with alterations in DDR pathways. Ahead of the meeting, experts completed a 27-question survey evaluating the key issues. The final recommendations herein should aid in facilitating clinical practice decisions on the management of DDR-deficient PDAC.

Keywords:  BRCA1/2; DNA damage repair; PARP inhibition; homologous repair deficiency; pancreatic ductal adenocarcinoma; platinum

DOI:  https://doi.org/10.3390/cancers13174259
Nat Commun. 2021 Sep 09. 12(1): 5248

Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.

Hema Adhikari, Walaa E Kattan, Shivesh Kumar, Pei Zhou, John F Hancock, Christopher M Counter.

The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRASG12C inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers.

DOI: https://doi.org/10.1038/s41467-021-25523-5
Eur J Epidemiol. 2021 Sep 05.

Low and high pancreatic amylase is associated with pancreatic cancer and chronic pancreatitis.

Signe E J Hansen, Anne Langsted, Anette Varbo, Christian M Madsen, Anne Tybjærg-Hansen, Børge G Nordestgaard.

  Incidences of pancreatic cancer and acute and chronic pancreatitis are rising globally, and often no curative treatment is available at the time of diagnosis. We tested the hypothesis that low and high plasma concentrations of pancreatic amylase are associated with increased risk of pancreatic cancer, acute pancreatitis, and chronic pancreatitis in the general population. We included 101,765 individuals (55% women) aged 20-100 years from the Copenhagen General Population Study with baseline measurements of plasma pancreatic amylase. After recruitment in 2004-2015 during a median 9 years of follow-up (range 0-15), we collected information about diagnoses of pancreatic cancer, acute pancreatitis, and chronic pancreatitis from the national Danish Patient Registry, the national Danish Cancer Registry, and the national Danish Causes of Death Registry. The median age was 58 years (interquartile range: 48-67) and the median plasma pancreatic amylase 32 U/L (26-40). During follow-up, 442 individuals were diagnosed with pancreatic cancer, 282 with chronic pancreatitis, and 401 with acute pancreatitis. Compared to individuals with pancreatic amylase levels in the 41st-60th percentiles, those with extreme low (1st-2.5th percentiles) and extreme high (97.5th-100th percentiles) pancreatic amylase had hazard ratios of 2.4 (95% confidence interval; 1.6-3.6) and 2.2 (1.4-3.7) for pancreatic cancer, of 1.8 (1.1-3.3) and 3.2 (1.8-5.6) for chronic pancreatitis, and of 1.1 (0.6-1.8) and 1.5 (0.8-2.7) for acute pancreatitis, respectively. In apparently healthy individuals from the general population, extreme low and extreme high plasma pancreatic amylase were associated with 2-threefold higher risk of both pancreatic cancer and chronic pancreatitis.

Keywords:  Biochemistry; Epidemiology; Gastroenterology; General population study; Pancreas; Risk factor

DOI:  https://doi.org/10.1007/s10654-021-00801-0
Nature. 2021 09;597(7875): 250-255

Cells of the human intestinal tract mapped across space and time.

Rasa Elmentaite, Natsuhiko Kumasaka, Kenny Roberts, Aaron Fleming, Emma Dann, Hamish W King, Vitalii Kleshchevnikov, Monika Dabrowska, Sophie Pritchard, Liam Bolt, Sara F Vieira, Lira Mamanova, Ni Huang, Francesca Perrone, Issac Goh Kai'En, Steven N Lisgo, Matilda Katan, Steven Leonard, Thomas R W Oliver, C Elizabeth Hook, Komal Nayak, Lia S Campos, Cecilia Domínguez Conde, Emily Stephenson, Justin Engelbert, Rachel A Botting, Krzysztof Polanski, Stijn van Dongen, Minal Patel, Michael D Morgan, John C Marioni, Omer Ali Bayraktar, Kerstin B Meyer, Xiaoling He, Roger A Barker, Holm H Uhlig, Krishnaa T Mahbubani, Kourosh Saeb-Parsy, Matthias Zilbauer, Menna R Clatworthy, Muzlifah Haniffa, Kylie R James, Sarah A Teichmann.

The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung's disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.

DOI: https://doi.org/10.1038/s41586-021-03852-1
Elife. 2021 Sep 06. pii: e66198. [Epub ahead of print]10

Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines.

Kevin Hu, Mahmoud Ghandi, Franklin W Huang.

  In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1,299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality.

Keywords:  cancer biology; computational biology; human; systems biology

DOI:  https://doi.org/10.7554/eLife.66198
PLoS One. 2021 ;16(9): e0257084

Proteogenomic analysis of pancreatic cancer subtypes.

Doris Kafita, Panji Nkhoma, Mildred Zulu, Musalula Sinkala.

Pancreatic cancer remains a significant public health problem with an ever-rising incidence of disease. Cancers of the pancreas are characterised by various molecular aberrations, including changes in the proteomics and genomics landscape of the tumour cells. Therefore, there is a need to identify the proteomic landscape of pancreatic cancer and the specific genomic and molecular alterations associated with disease subtypes. Here, we carry out an integrative bioinformatics analysis of The Cancer Genome Atlas dataset, including proteomics and whole-exome sequencing data collected from pancreatic cancer patients. We apply unsupervised clustering on the proteomics dataset to reveal the two distinct subtypes of pancreatic cancer. Using functional and pathway analysis based on the proteomics data, we demonstrate the different molecular processes and signalling aberrations of the pancreatic cancer subtypes. In addition, we explore the clinical characteristics of these subtypes to show differences in disease outcome. Using datasets of mutations and copy number alterations, we show that various signalling pathways previously associated with pancreatic cancer are altered among both subtypes of pancreatic tumours, including the Wnt pathway, Notch pathway and PI3K-mTOR pathways. Altogether, we reveal the proteogenomic landscape of pancreatic cancer subtypes and the altered molecular processes that can be leveraged to devise more effective treatments.

DOI: https://doi.org/10.1371/journal.pone.0257084
Nat Rev Clin Oncol. 2021 Sep 06.

Clinical and therapeutic relevance of cancer-associated fibroblasts.

Yang Chen, Kathleen M McAndrews, Raghu Kalluri.

Cancer-associated fibroblasts (CAFs) found in primary and metastatic tumours are highly versatile, plastic and resilient cells that are actively involved in cancer progression through complex interactions with other cell types in the tumour microenvironment. As well as generating extracellular matrix components that contribute to the structure and function of the tumour stroma, CAFs undergo epigenetic changes to produce secreted factors, exosomes and metabolites that influence tumour angiogenesis, immunology and metabolism. Because of their putative pro-oncogenic functions, CAFs have long been considered an attractive therapeutic target; however, clinical trials of treatment strategies targeting CAFs have mostly ended in failure and, in some cases, accelerated cancer progression and resulted in inferior survival outcomes. Importantly, CAFs are heterogeneous cells and their characteristics and interactions with other cell types might change dynamically as cancers evolve. Studies involving single-cell RNA sequencing and novel mouse models have increased our understanding of CAF diversity, although the context-dependent roles of different CAF populations and their interchangeable plasticity remain largely unknown. Comprehensive characterization of the tumour-promoting and tumour-restraining activities of CAF subtypes, including how these complex bimodal functions evolve and are subjugated by neoplastic cells during cancer progression, might facilitate the development of novel diagnostic and therapeutic approaches. In this Review, the clinical relevance of CAFs is summarized with an emphasis on their value as prognosis factors and therapeutic targets.

DOI: https://doi.org/10.1038/s41571-021-00546-5
Aging (Albany NY). 2021 Aug 17. 13(16): 20229-20245

Autophagic flux in cancer cells at the invasive front in the tumor-stroma border.

Fei Yan, Xuexi Zhang, Rongying Tan, Mingchen Li, Zengtuan Xiao, Hao Wang, Zhenfa Zhang, Zhenyi Ma, Zhe Liu.

  Cancer cells at the invasive front directly interact with stromal tissue that provides a microenvironment with mechanical, nutrient, and oxygen supply characteristics distinct from those of intratumoral tissues. It has long been known that cancer cells at the invasive front and cancer cells inside the tumor body exhibit highly differentiated functions and behaviors. However, it is unknown whether cancer cells at different locations exhibit a variety of autophagic flux, an important catabolic process to maintain cellular homeostasis in response to environmental changes. Here, using transmission electron microscopy (TEM), we found that invading cancer cells at the invasive front, which show mesenchymal transcriptomic traits, exhibit higher autophagic flux than cancer cells inside the tumor body in human primary non-small cell lung cancer (NSCLC) tissues. This autophagic feature was further confirmed by a live cell autophagic flux monitoring system combined with a 3D organotypic invasion coculture system. Additionally, the increased autophagic flux endows cancer cells with invasive behavior and positively correlates with the advanced tumor stages and the reduced survival period of lung cancer patients. These findings expand the understanding of autophagic dynamics during cancer invasion.

Keywords:  autophagy; invasion; invasive front; lung cancer; tumor-stroma border

DOI:  https://doi.org/10.18632/aging.203406
Cell Rep. 2021 Sep 07. pii: S2211-1247(21)01033-0. [Epub ahead of print]36(10): 109595

Chronic stress primes innate immune responses in mice and humans.

Tessa J Barrett, Emma M Corr, Coen van Solingen, Florencia Schlamp, Emily J Brown, Graeme J Koelwyn, Angela H Lee, Lianne C Shanley, Tanya M Spruill, Fazli Bozal, Annika de Jong, Alexandra A C Newman, Kamelia Drenkova, Michele Silvestro, Bhama Ramkhelawon, Harmony R Reynolds, Judith S Hochman, Matthias Nahrendorf, Filip K Swirski, Edward A Fisher, Jeffrey S Berger, Kathryn J Moore.

  Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.

Keywords:  inflammation; metabolism; monocytes; priming; psychological stress; women

DOI:  https://doi.org/10.1016/j.celrep.2021.109595
Nat Rev Cancer. 2021 Sep 10.

Stress and cancer: mechanisms, significance and future directions.

Anabel Eckerling, Itay Ricon-Becker, Liat Sorski, Elad Sandbank, Shamgar Ben-Eliyahu.

The notion that stress and cancer are interlinked has dominated lay discourse for decades. More recent animal studies indicate that stress can substantially facilitate cancer progression through modulating most hallmarks of cancer, and molecular and systemic mechanisms mediating these effects have been elucidated. However, available clinical evidence for such deleterious effects is inconsistent, as epidemiological and stress-reducing clinical interventions have yielded mixed effects on cancer mortality. In this Review, we describe and discuss specific mediating mechanisms identified by preclinical research, and parallel clinical findings. We explain the discrepancy between preclinical and clinical outcomes, through pointing to experimental strengths leveraged by animal studies and through discussing methodological and conceptual obstacles that prevent clinical studies from reflecting the impacts of stress. We suggest approaches to circumvent such obstacles, based on targeting critical phases of cancer progression that are more likely to be stress-sensitive; pharmacologically limiting adrenergic-inflammatory responses triggered by medical procedures; and focusing on more vulnerable populations, employing personalized pharmacological and psychosocial approaches. Recent clinical trials support our hypothesis that psychological and/or pharmacological inhibition of excess adrenergic and/or inflammatory stress signalling, especially alongside cancer treatments, could save lives.

DOI: https://doi.org/10.1038/s41568-021-00395-5
Int Rev Cell Mol Biol. 2021 ;pii: S1937-6448(21)00076-9. [Epub ahead of print]364 1-110

DNA methylation and histone variants in aging and cancer.

Adèle Mangelinck, Carl Mann.

  Aging-related diseases such as cancer can be traced to the accumulation of molecular disorder including increased DNA mutations and epigenetic drift. We provide a comprehensive review of recent results in mice and humans on modifications of DNA methylation and histone variants during aging and in cancer. Accumulated errors in DNA methylation maintenance lead to global decreases in DNA methylation with relaxed repression of repeated DNA and focal hypermethylation blocking the expression of tumor suppressor genes. Epigenetic clocks based on quantifying levels of DNA methylation at specific genomic sites is proving to be a valuable metric for estimating the biological age of individuals. Histone variants have specialized functions in transcriptional regulation and genome stability. Their concentration tends to increase in aged post-mitotic chromatin, but their effects in cancer are mainly determined by their specialized functions. Our increased understanding of epigenetic regulation and their modifications during aging has motivated interventions to delay or reverse epigenetic modifications using the epigenetic clocks as a rapid readout for efficacity. Similarly, the knowledge of epigenetic modifications in cancer is suggesting new approaches to target these modifications for cancer therapy.

Keywords:  Aging; Cancer; DNA methylation; Epigenetic clocks; Epigenetics; Histone variants; Senescence

DOI:  https://doi.org/10.1016/bs.ircmb.2021.06.002
Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2113647118. [Epub ahead of print]118(37):

p62 condensates are a hub for proteasome-mediated protein turnover in the nucleus.

Pia Erdbrügger, Florian Wilfling.

DOI: https://doi.org/10.1073/pnas.2113647118
Comput Struct Biotechnol J. 2021 ;19 4759-4769

Protein-gene Expression Nexus: Comprehensive characterization of human cancer cell lines with proteogenomic analysis.

Daejin Hyung, Min-Jeong Baek, Jongkeun Lee, Juyeon Cho, Hyoun Sook Kim, Charny Park, Soo Young Cho.

  Researchers have gained new therapeutic insights using multi-omics platform approaches to study DNA, RNA, and proteins of comprehensively characterized human cancer cell lines. To improve our understanding of the molecular features associated with oncogenic modulation in cancer, we proposed a proteogenomic database for human cancer cell lines, called Protein-gene Expression Nexus (PEN). We have expanded the characterization of cancer cell lines to include genetic, mRNA, and protein data of 145 cancer cell lines from various public studies. PEN contains proteomic and phosphoproteomic data on 4,129,728 peptides, 13,862 proteins, 7,138 phosphorylation site-associated genomic variations, 117 studies, and 12 cancer. We analyzed functional characterizations along with the integrated datasets, such as cis/trans association for copy number alteration (CNA), single amino acid variation for coding genes, post-translation modification site variation for Single Amino Acid Variation, and novel peptide expression for noncoding regions and fusion genes. PEN provides a user-friendly interface for searching, browsing, and downloading data and also supports the visualization of genome-wide association between CNA and expression, novel peptide landscape, mRNA-protein abundance, and functional annotation. Together, this dataset and PEN data portal provide a resource to accelerate cancer research using model cancer cell lines. PEN is freely accessible at http://combio.snu.ac.kr/pen.

Keywords:  Cancer cell line; Phosphoproteomics; Proteogenomics; Single amino acid variation; Systems biology

DOI:  https://doi.org/10.1016/j.csbj.2021.08.022
Nat Rev Endocrinol. 2021 Sep 10.

Autophagy in metabolic disease and ageing.

Munehiro Kitada, Daisuke Koya.

Autophagy is an evolutionarily conserved, lysosome-dependent catabolic process whereby cytoplasmic components, including damaged organelles, protein aggregates and lipid droplets, are degraded and their components recycled. Autophagy has an essential role in maintaining cellular homeostasis in response to intracellular stress; however, the efficiency of autophagy declines with age and overnutrition can interfere with the autophagic process. Therefore, conditions such as sarcopenic obesity, insulin resistance and type 2 diabetes mellitus (T2DM) that are characterized by metabolic derangement and intracellular stresses (including oxidative stress, inflammation and endoplasmic reticulum stress) also involve the accumulation of damaged cellular components. These conditions are prevalent in ageing populations. For example, sarcopenia is an age-related loss of skeletal muscle mass and strength that is involved in the pathogenesis of both insulin resistance and T2DM, particularly in elderly people. Impairment of autophagy results in further aggravation of diabetes-related metabolic derangements in insulin target tissues, including the liver, skeletal muscle and adipose tissue, as well as in pancreatic β-cells. This Review summarizes the role of autophagy in the pathogenesis of metabolic diseases associated with or occurring in the context of ageing, including insulin resistance, T2DM and sarcopenic obesity, and describes its potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41574-021-00551-9
Aging (Albany NY). 2021 Sep 07. 13(undefined):

Glutamine promotes escape from therapy-induced senescence in tumor cells.

Francesco Pacifico, Nadia Badolati, Stefano Mellone, Mariano Stornaiuolo, Antonio Leonardi, Elvira Crescenzi.

  Therapy-induced senescence (TIS) is a major cellular response to anticancer therapies. While induction of a persistent growth arrest would be a desirable outcome in cancer therapy, it has been shown that, unlike normal cells, cancer cells are able to evade the senescence cell cycle arrest and to resume proliferation, likely contributing to tumor relapse. Notably, cells that escape from TIS acquire a plastic, stem cell-like phenotype. The metabolic dependencies of cells that evade senescence have not been thoroughly studied. In this study, we show that glutamine depletion inhibits escape from TIS in all cell lines studied, and reduces the stem cell subpopulation. In line with a metabolic reliance on glutamine, escaped clones overexpress the glutamine transporter SLC1A5. We also demonstrate a central role of glutamine synthetase that mediates resistance to glutamine deprivation, conferring independence from exogenous glutamine. Finally, rescue experiments demonstrate that glutamine provides nitrogen for nucleotides biosynthesis in cells that escape from TIS, but also suggest a critical involvement of glutamine in other metabolic and non-metabolic pathways. On the whole, these results reveal a metabolic vulnerability of cancer stem cells that recover proliferation after exposure to anticancer therapies, which could be exploited to prevent tumor recurrence.

Keywords:  cancer stem cells; escape; glutamine; glutamine synthetase; therapy-induced senescence

DOI:  https://doi.org/10.18632/aging.203495
Front Bioeng Biotechnol. 2021 ;9 701039

Identification of Key mRNAs as Prediction Models for Early Metastasis of Pancreatic Cancer Based on LASSO.

Ke Xue, Huilin Zheng, Xiaowen Qian, Zheng Chen, Yangjun Gu, Zhenhua Hu, Lei Zhang, Jian Wan.

  Pancreatic cancer is a highly malignant and metastatic tumor of the digestive system. Even after surgical removal of the tumor, most patients are still at risk of metastasis. Therefore, screening for metastatic biomarkers can identify precise therapeutic intervention targets. In this study, we analyzed 96 pancreatic cancer samples from The Cancer Genome Atlas (TCGA) without metastasis or with metastasis after R0 resection. We also retrieved data from metastatic pancreatic cancer cell lines from Gene Expression Omnibus (GEO), as well as collected sequencing data from our own cell lines, BxPC-3 and BxPC-3-M8. Finally, we analyzed the expression of metastasis-related genes in different datasets by the Limma and edgeR packages in R software, and enrichment analysis of differential gene expression was used to gain insight into the mechanism of pancreatic cancer metastasis. Our analysis identified six genes as risk factors for predicting metastatic status by LASSO regression, including zinc finger BED-Type Containing 2 (ZBED2), S100 calcium-binding protein A2 (S100A2), Jagged canonical Notch ligand 1 (JAG1), laminin subunit gamma 2 (LAMC2), transglutaminase 2 (TGM2), and the transcription factor hepatic leukemia factor (HLF). We used these six EMT-related genes to construct a risk-scoring model. The receiver operating characteristic (ROC) curve showed that the risk score could better predict the risk of metastasis. Univariate and multivariate Cox regression analyses revealed that the risk score was also an important predictor of pancreatic cancer. In conclusion, 6-mRNA expression is a potentially valuable method for predicting pancreatic cancer metastasis, assessing clinical outcomes, and facilitating future personalized treatment for patients with ductal adenocarcinoma of the pancreas (PDAC).

Keywords:  EMT; bioinformatics; metastasis; pancreatic cancer; precision medicine

DOI:  https://doi.org/10.3389/fbioe.2021.701039