bims-cagime 2023-05-07 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2023–05–07
thirty papers selected by
Kıvanç Görgülü, Technical University of Munich

Skeletal muscle omics signatures in cancer cachexia: perspectives and opportunities.
Dissecting metastasis using preclinical models and methods.
Hematopoietic progenitor kinase 1 inhibits the development and progression of pancreatic intraepithelial neoplasia.
Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.
EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance.
Organism-wide, cell-type-specific secretome mapping of exercise training in mice.
Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.
Effects of S-pindolol in mouse pancreatic and lung cancer cachexia models.
p73 activates transcriptional signatures of basal lineage identity and ciliogenesis in pancreatic ductal adenocarcinoma.
Impairment of aryl hydrocarbon receptor signalling promotes hepatic disorders in cancer cachexia.
Remote control of autophagy and metabolism in the liver.
Machine learning versus regression for prediction of sporadic pancreatic cancer.
PARKIN UBIQUITINATION OF KINDLIN-2 ENABLES MITOCHONDRIA-ASSOCIATED METASTASIS SUPPRESSION.
How thought itself can drive tumour growth.
TPX2 expression as a negative predictor of gemcitabine efficacy in pancreatic cancer.
A phosphate-sensing organelle regulates phosphate and tissue homeostasis.
Career pathways, part 11.
Three-dimensional analysis of human pancreatic cancer specimens by phase-contrast based X-ray tomography - the next dimension of diagnosis.
Untangling the mechanisms of cancer predisposition.
Sirtuin 6 is required for the integrated stress response and resistance to inhibition of transcriptional cyclin-dependent kinases.
A Multi-omic Analysis of the Human Lung Reveals Distinct Cell Specific Aging and Senescence Molecular Programs.
Monitoring AKT activity and targeting in live tissue and disease contexts using a real-time Akt-FRET biosensor mouse.
Mitochondrial protein import clogging as a mechanism of disease.
Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET.
Mitigating age-related somatic mutation burden.
Physical basis of the cell size scaling laws.
Molecular basis of translation termination at noncanonical stop codons in human mitochondria.
Selective Visualization of Tumor Cell Membranes and Tumors with a Viscosity-Sensitive Plasma Membrane Probe.
CysDB: a human cysteine database based on experimental quantitative chemoproteomics.
CellMinerCDB: NCATS is a Web-Based Portal Integrating Public Cancer Cell Line Databases for Pharmacogenomic Explorations.

J Natl Cancer Inst Monogr. 2023 May 04. 2023(61): 30-42

Skeletal muscle omics signatures in cancer cachexia: perspectives and opportunities.

L Anne Gilmore, Traci L Parry, Gwendolyn A Thomas, Andy V Khamoui.

Cachexia is a life-threatening complication of cancer that occurs in up to 80% of patients with advanced cancer. Cachexia reflects the systemic consequences of cancer and prominently features unintended weight loss and skeletal muscle wasting. Cachexia impairs cancer treatment tolerance, lowers quality of life, and contributes to cancer-related mortality. Effective treatments for cancer cachexia are lacking despite decades of research. High-throughput omics technologies are increasingly implemented in many fields including cancer cachexia to stimulate discovery of disease biology and inform therapy choice. In this paper, we present selected applications of omics technologies as tools to study skeletal muscle alterations in cancer cachexia. We discuss how comprehensive, omics-derived molecular profiles were used to discern muscle loss in cancer cachexia compared with other muscle-wasting conditions, to distinguish cancer cachexia from treatment-related muscle alterations, and to reveal severity-specific mechanisms during the progression of cancer cachexia from early toward severe disease.

DOI: https://doi.org/10.1093/jncimonographs/lgad006
Nat Rev Cancer. 2023 May 03.

Dissecting metastasis using preclinical models and methods.

Jess D Hebert, Joel W Neal, Monte M Winslow.

Metastasis has long been understood to lead to the overwhelming majority of cancer-related deaths. However, our understanding of the metastatic process, and thus our ability to prevent or eliminate metastases, remains frustratingly limited. This is largely due to the complexity of metastasis, which is a multistep process that likely differs across cancer types and is greatly influenced by many aspects of the in vivo microenvironment. In this Review, we discuss the key variables to consider when designing assays to study metastasis: which source of metastatic cancer cells to use and where to introduce them into mice to address different questions of metastasis biology. We also examine methods that are being used to interrogate specific steps of the metastatic cascade in mouse models, as well as emerging techniques that may shed new light on previously inscrutable aspects of metastasis. Finally, we explore approaches for developing and using anti-metastatic therapies, and how mouse models can be used to test them.

DOI: https://doi.org/10.1038/s41568-023-00568-4
J Clin Invest. 2023 May 04. pii: e163873. [Epub ahead of print]

Hematopoietic progenitor kinase 1 inhibits the development and progression of pancreatic intraepithelial neoplasia.

Hua Wang, Rohan Moniruzzaman, Lei Li, Baoan Ji, Yi Liu, Xiangsheng Zuo, Reza Abbasgholizadeh, Jun Zhao, Guangchao Liu, Ruiqi Wang, Hongli Tang, Ryan Sun, Xiaoping Su, Tse-Hua Tan, Anirban Maitra, Huamin Wang.

  Ras plays an essential role in the development of acinar to ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC). However, mutant Kras is an inefficient driver for PDAC development. The switching mechanisms from low Ras activity to high Ras activity that is required for development and progression of pancreatic intraepithelial neoplasia (PanIN) are unclear. In this study, we found that HPK1 was upregulated during pancreatic injury and ADM. HPK1 interacted with the SH3 domain and phosphorylated Ras GTPase activating protein (RasGAP) and upregulated RasGAP activity. Using the transgenic mouse models of HPK1 or M46, a kinase-dead mutant of HPK1, we showed that HPK1 inhibited Ras activity and its downstream signaling and regulated acinar cell plasticity. M46 promoted the development of ADM and PanINs. Expression of M46 in KrasG12D;Bac mice promoted the infiltration of myeloid-derived suppressor cells and macrophages, inhibited the infiltration of T cells, and accelerated the progression of PanINs to invasive and metastatic PDAC, while HPK1 attenuated mutant Kras-driven PanIN progression. Our results showed that HPK1 plays an important role in ADM and the progression of PanINs by regulating Ras signaling. Loss of HPK1 kinase activity promotes an immunosuppressive tumor microenvironment and accelerates the progression of PanINs to PDAC.

Keywords:  Gastroenterology; Mouse models; Protein kinases; Tumor suppressors

DOI:  https://doi.org/10.1172/JCI163873
J Med Genet. 2023 May 02. pii: jmg-2022-108910. [Epub ahead of print]

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

Chiara Corradi, Giulia Lencioni, Manuel Gentiluomo, Alessio Felici, Anna Latiano, Gediminas Kiudelis, Casper H J van Eijck, Katalin Marta, Rita T Lawlor, Francesca Tavano, Ugo Boggi, Frederike Dijk, Giulia Martina Cavestro, Roel C H Vermeulen, Thilo Hackert, Maria Chiara Petrone, Faik Güntac Uzunoğlu, Livia Archibugi, Jakob R Izbicki, Luca Morelli, Alessandro Zerbi, Stefano Landi, Hannah Stocker, Renata Talar-Wojnarowska, Gregorio Di Franco, Péter Hegyi, Cosimo Sperti, Silvia Carrara, Gabriele Capurso, Maria Gazouli, Hermann Brenner, Stefania Bunduc, Olivier Busch, Francesco Perri, Martin Oliverius, Péter Jeno Hegyi, Mara Goetz, Pasquale Scognamiglio, Andrea Mambrini, Paolo Giorgio Arcidiacono, Edita Kreivenaite, Juozas Kupcinskas, Tamas Hussein, Stefano Ermini, Anna Caterina Milanetto, Pavel Vodicka, Vytautas Kiudelis, Viktor Hlaváč, Pavel Soucek, George E Theodoropoulos, Daniela Basso, John P Neoptolemos, Mateus Nóbrega Aoki, Raffaele Pezzilli, Claudio Pasquali, Roger Chammas, Sabrina Gloria Giulia Testoni, Beatrice Mohelnikova-Duchonova, Maurizio Lucchesi, Cosmeri Rizzato, Federico Canzian, Daniele Campa.

   INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate.
MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase.
RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1.
CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

Keywords:  DNA Methylation; Genetic Variation; Genetics; Germ-Line Mutation; Molecular Epidemiology

DOI:  https://doi.org/10.1136/jmg-2022-108910
Nat Cancer. 2023 May 04.

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance.

Loretah Chibaya, Katherine C Murphy, Kelly D DeMarco, Sneha Gopalan, Haibo Liu, Chaitanya N Parikh, Yvette Lopez-Diaz, Melissa Faulkner, Junhui Li, John P Morris, Yu-Jui Ho, Sachliv K Chana, Janelle Simon, Wei Luan, Amanda Kulick, Elisa de Stanchina, Karl Simin, Lihua Julie Zhu, Thomas G Fazzio, Scott W Lowe, Marcus Ruscetti.

Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor natural killer (NK) cell and T cell immunity. In the present study, we found that the pancreas tumor microenvironment suppresses NK cell and T cell surveillance after therapy-induced senescence through enhancer of zeste homolog 2 (EZH2)-mediated epigenetic repression of proinflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK cell and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in patients with PDAC. These results demonstrate that EZH2 represses the proinflammatory SASP and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC.

DOI: https://doi.org/10.1038/s43018-023-00553-8
Cell Metab. 2023 Apr 28. pii: S1550-4131(23)00138-9. [Epub ahead of print]

Organism-wide, cell-type-specific secretome mapping of exercise training in mice.

Wei Wei, Nicholas M Riley, Xuchao Lyu, Xiaotao Shen, Jing Guo, Steffen H Raun, Meng Zhao, Maria Dolores Moya-Garzon, Himanish Basu, Alan Sheng-Hwa Tung, Veronica L Li, Wentao Huang, Amanda L Wiggenhorn, Katrin J Svensson, Michael P Snyder, Carolyn R Bertozzi, Jonathan Z Long.

  There is a significant interest in identifying blood-borne factors that mediate tissue crosstalk and function as molecular effectors of physical activity. Although past studies have focused on an individual molecule or cell type, the organism-wide secretome response to physical activity has not been evaluated. Here, we use a cell-type-specific proteomic approach to generate a 21-cell-type, 10-tissue map of exercise training-regulated secretomes in mice. Our dataset identifies >200 exercise training-regulated cell-type-secreted protein pairs, the majority of which have not been previously reported. Pdgfra-cre-labeled secretomes were the most responsive to exercise training. Finally, we show anti-obesity, anti-diabetic, and exercise performance-enhancing activities for proteoforms of intracellular carboxylesterases whose secretion from the liver is induced by exercise training.

Keywords:  CES2; cell type; energy metabolism; exercise; exercise performance; hepatokine; obesity; secretome; tissue crosstalk

DOI:  https://doi.org/10.1016/j.cmet.2023.04.011
Sci Adv. 2023 May 03. 9(18): eadf0138

Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.

Ramya S Kuna, Avi Kumar, Karl A Wessendorf-Rodriguez, Hector Galvez, Courtney R Green, Grace H McGregor, Thekla Cordes, Reuben J Shaw, Robert U Svensson, Christian M Metallo.

Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as nutrient availability fluctuates, so understanding how cells maintain acetyl-CoA homeostasis under such stresses is critically important. To this end, we applied 13C isotope tracing cell lines deficient in these mitochondrial [ATP-citrate lyase (ACLY)]-, cytosolic [acetyl-CoA synthetase (ACSS2)]-, and peroxisomal [peroxisomal biogenesis factor 5 (PEX5)]-dependent pathways. ACLY knockout in multiple cell lines reduced fatty acid synthesis and increased reliance on extracellular lipids or acetate. Knockout of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation, suggesting that alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX5 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA for lipogenesis and histone acetylation in cells lacking ACLY, highlighting a role for inter-organelle cross-talk in supporting cell survival in response to nutrient fluctuations.

DOI: https://doi.org/10.1126/sciadv.adf0138
J Cachexia Sarcopenia Muscle. 2023 May 02.

Effects of S-pindolol in mouse pancreatic and lung cancer cachexia models.

Jochen Springer, Queralt Jové, Edson Alves de Lima Junior, Natalia Álvarez Ladrón, Francisco Javier López-Soriano, Silvia Busquets, Josep M Argiles, Daniel L Marks.

   BACKGROUND: It is known that S-pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals.
METHODS: Here, we tested 3 mg/kg/day of S-pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC).
RESULTS: Treatment of mice with 3 mg/kg/day of S-pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo-treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (-0.9 ± 1.0 vs. -2.2 ± 1.4 g for S-pindolol and placebo, respectively, P < 0.05) and around a third of the lean mass lost by tumour-bearing controls (-0.4 ± 1.0 vs. -1.5 ± 1.5 g for S-pindolol and placebo, respectively, P < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S-pindolol tumour-bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S-pindolol-treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S-pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S-pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S-pindolol-treated mice improved by 32.7 ± 18.5 g, tumour-bearing mice only show minimal improvements (7.3 ± 19.4 g, P < 0.01).
CONCLUSIONS: S-pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength.

Keywords:  S-pindolol; body weight; cancer cachexia; grip strength; lung cancer; pancreatic cancer

DOI:  https://doi.org/10.1002/jcsm.13249
bioRxiv. 2023 Apr 21. pii: 2023.04.20.537667. [Epub ahead of print]

p73 activates transcriptional signatures of basal lineage identity and ciliogenesis in pancreatic ductal adenocarcinoma.

Stella K Hur, Tim D D Somerville, Xiaoli S Wu, Diogo Maia-Silva, Osama E Demerdash, David A Tuveson, Faiyaz Notta, Christopher R Vakoc.

During the progression of pancreatic ductal adenocarcinoma (PDAC), tumor cells are known to acquire transcriptional and morphological properties of the basal (also known as squamous) epithelial lineage, which leads to more aggressive disease characteristics. Here, we show that a subset of basal-like PDAC tumors aberrantly express p73 (TA isoform), which is a known transcriptional activator of basal lineage identity, ciliogenesis, and tumor suppression in normal tissue development. Using gain- and loss- of function experiments, we show that p73 is necessary and sufficient to activate genes related to basal identity (e.g. KRT5 ), ciliogenesis (e.g. FOXJ1 ), and p53-like tumor suppression (e.g. CDKN1A ) in human PDAC models. Owing to the paradoxical combination of oncogenic and tumor suppressive outputs of this transcription factor, we propose that PDAC cells express a low level of p73 that is optimal for promoting lineage plasticity without severe impairment of cell proliferation. Collectively, our study reinforces how PDAC cells exploit master regulators of the basal epithelial lineage during disease progression.

DOI: https://doi.org/10.1101/2023.04.20.537667
J Cachexia Sarcopenia Muscle. 2023 May 01.

Impairment of aryl hydrocarbon receptor signalling promotes hepatic disorders in cancer cachexia.

Adeline Dolly, Sarah A Pötgens, Morgane M Thibaut, Audrey M Neyrinck, Gabriela S de Castro, Chloé Galbert, Camille Lefevre, Elisabeth Wyart, Silvio P Gomes, Daniela C Gonçalves, Nicolas Lanthier, Pamela Baldin, Joshua R Huot, Andrea Bonetto, Marília Seelaender, Nathalie M Delzenne, Harry Sokol, Laure B Bindels.

   BACKGROUND: The aryl hydrocarbon receptor (AHR) is expressed in the intestine and liver, where it has pleiotropic functions and target genes. This study aims to explore the potential implication of AHR in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. Specifically, we tested the hypothesis that targeting AHR can alleviate cachectic features, particularly through the gut-liver axis.
METHODS: AHR pathways were explored in multiple tissues from four experimental mouse models of cancer cachexia (C26, BaF3, MC38 and APCMin/+ ) and from non-cachectic mice (sham-injected mice and non-cachexia-inducing [NC26] tumour-bearing mice), as well as in liver biopsies from cancer patients. Cachectic mice were treated with an AHR agonist (6-formylindolo(3,2-b)carbazole [FICZ]) or an antibody neutralizing interleukin-6 (IL-6). Key mechanisms were validated in vitro on HepG2 cells.
RESULTS: AHR activation, reflected by the expression of Cyp1a1 and Cyp1a2, two major AHR target genes, was deeply reduced in all models (C26 and BaF3, P < 0.001; MC38 and APCMin/+ , P < 0.05) independently of anorexia. This reduction occurred early in the liver (P < 0.001; before the onset of cachexia), compared to the ileum and skeletal muscle (P < 0.01; pre-cachexia stage), and was intrinsically related to cachexia (C26 vs. NC26, P < 0.001). We demonstrate a differential modulation of AHR activation in the liver (through the IL-6/hypoxia-inducing factor 1α pathway) compared to the ileum (attributed to the decreased levels of indolic AHR ligands, P < 0.001), and the muscle. In cachectic mice, FICZ treatment reduced hepatic inflammation: expression of cytokines (Ccl2, P = 0.005; Cxcl2, P = 0.018; Il1b, P = 0.088) with similar trends at the protein levels, expression of genes involved in the acute-phase response (Apcs, P = 0.040; Saa1, P = 0.002; Saa2, P = 0.039; Alb, P = 0.003), macrophage activation (Cd68, P = 0.038) and extracellular matrix remodelling (Fga, P = 0.008; Pcolce, P = 0.025; Timp1, P = 0.003). We observed a decrease in blood glucose in cachectic mice (P < 0.0001), which was also improved by FICZ treatment (P = 0.026) through hepatic transcriptional promotion of a key marker of gluconeogenesis, namely, G6pc (C26 vs. C26 + FICZ, P = 0.029). Strikingly, these benefits on glycaemic disorders occurred independently of an amelioration of the gut barrier dysfunction. In cancer patients, the hepatic expression of G6pc was correlated to Cyp1a1 (Spearman's ρ = 0.52, P = 0.089) and Cyp1a2 (Spearman's ρ = 0.67, P = 0.020).
CONCLUSIONS: With this set of studies, we demonstrate that impairment of AHR signalling contributes to hepatic inflammatory and metabolic disorders characterizing cancer cachexia, paving the way for innovative therapeutic strategies in this context.

Keywords:  CYP1A1; CYP1A2; HIF1α; TIPARP; fibroblast growth factor 21

DOI:  https://doi.org/10.1002/jcsm.13246
Cell Metab. 2023 May 02. pii: S1550-4131(23)00136-5. [Epub ahead of print]35(5): 725-727

Remote control of autophagy and metabolism in the liver.

Nektarios Tavernarakis.

Systemic control of homeostatic processes is of fundamental importance for survival and adaptation in metazoans. In this issue of Cell Metabolism, Chen and colleagues identify and methodically dissect a signaling cascade that is mobilized by the agouti-related peptide (AgRP)-expressing neurons in the hypothalamus, to ultimately modulate autophagy and metabolism in the liver upon starvation.

DOI: https://doi.org/10.1016/j.cmet.2023.04.009
Pancreatology. 2023 Apr 27. pii: S1424-3903(23)00103-5. [Epub ahead of print]

Machine learning versus regression for prediction of sporadic pancreatic cancer.

Wansu Chen, Botao Zhou, Christie Y Jeon, Fagen Xie, Yu-Chen Lin, Rebecca K Butler, Yichen Zhou, Tiffany Q Luong, Eva Lustigova, Joseph R Pisegna, Bechien U Wu.

   BACKGROUND/OBJECTIVES: There is currently no widely accepted approach to identify patients at increased risk for sporadic pancreatic cancer (PC). We aimed to compare the performance of two machine-learning models with a regression-based model in predicting pancreatic ductal adenocarcinoma (PDAC), the most common form of PC.
METHODS: This retrospective cohort study consisted of patients 50-84 years of age enrolled in either Kaiser Permanente Southern California (KPSC, model training, internal validation) or the Veterans Affairs (VA, external testing) between 2008 and 2017. The performance of random survival forests (RSF) and eXtreme gradient boosting (XGB) models were compared to that of COX proportional hazards regression (COX). Heterogeneity of the three models were assessed.
RESULTS: The KPSC and the VA cohorts consisted of 1.8 and 2.7 million patients with 1792 and 4582 incident PDAC cases within 18 months, respectively. Predictors selected into all three models included age, abdominal pain, weight change, and glycated hemoglobin (A1c). Additionally, RSF selected change in alanine transaminase (ALT), whereas the XGB and COX selected the rate of change in ALT. The COX model appeared to have lower AUC (KPSC: 73.7, 95% CI 71.0-76.4; VA: 70.6, 69.9-71.4), compared to those of RSF (KPSC: 76.7, 74.4-79.1; VA: 73.1, 72.4-73.9) and XGB (KPSC: 77.9, 75.5-80.2; VA: 74.2, 73.5-75.0). Among patients with top 5% predicted risk from all three models (N = 29,663), 117 developed PDAC, of which RSF, XGB and COX captured 84 (9 unique), 87 (4 unique), 87 (19 unique) cases, respectively.
CONCLUSIONS: The three models complement each other, but each has unique contributions.

Keywords:  Machine learning versus regression; Pancreatic cancer; Random survival forest; Risk prediction; eXtreme gradient boosting

DOI:  https://doi.org/10.1016/j.pan.2023.04.009
J Biol Chem. 2023 May 02. pii: S0021-9258(23)01802-1. [Epub ahead of print] 104774

PARKIN UBIQUITINATION OF KINDLIN-2 ENABLES MITOCHONDRIA-ASSOCIATED METASTASIS SUPPRESSION.

Minjeong Yeon, Irene Bertolini, Ekta Agarwal, Jagadish C Ghosh, Hsin-Yao Tang, David W Speicher, Frederick Keeney, Khalid Sossey-Alaoui, Elzbieta Pluskota, Katarzyna Bialkowska, Edward F Plow, Lucia R Languino, Emmanuel Skordalakes, M Cecilia Caino, Dario C Altieri.

  Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitin ligase altered in Parkinson's Disease (PD), forms a complex with the regulator of cell motility, Kindlin-2 (K2) at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-ECM interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions or apoptosis. Expression of a Parkin ubiquitination-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 ubiquitination drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene and its ubiquitination by Parkin enables mitochondria-associated metastasis suppression.

Keywords:  Kindlin-2; Parkin; metastasis suppression; tumor cell motility; ubiquitination

DOI:  https://doi.org/10.1016/j.jbc.2023.104774
Nature. 2023 May 03.

How thought itself can drive tumour growth.

George M Ibrahim, Michael D Taylor.



Keywords:  Cancer; Medical research; Neuroscience

DOI:  https://doi.org/10.1038/d41586-023-01387-1
Br J Cancer. 2023 May 04.

TPX2 expression as a negative predictor of gemcitabine efficacy in pancreatic cancer.

Michael Guenther, Sai Agash Surendran, Michael Haas, Volker Heinemann, Michael von Bergwelt-Baildon, Jutta Engel, Jens Werner, Stefan Boeck, Steffen Ormanns.

BACKGROUND: Targeting protein for Xenopus kinesin-like protein 2 (TPX2) overexpression in human tumours is associated with increased malignancy. Its effect on gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) has not been studied yet.
METHODS: The prognostic impact of TPX2 expression was examined in the tumour tissue of 139 patients with advanced PDAC (aPDAC) treated within the AIO-PK0104 trial or translational trials and of 400 resected PDAC (rPDAC) patients. The findings were validated using RNAseq data of 149 resected PDAC patients.
RESULTS: In the aPDAC cohorts, 13.7% of all samples showed high TPX2 expression, conferring significantly shorter progression-free survival (PFS, HR 5.25, P < 0.001) and overall survival times (OS, HR 4.36, P < 0.001) restricted to gemcitabine-based treated patients (n = 99). In the rPDAC cohort, 14.5% of all samples showed high TPX2 expression, conferring significantly shorter disease-free survival times (DFS, HR 2.56, P < 0.001) and OS times (HR 1.56, P = 0.04) restricted to patients treated with adjuvant gemcitabine. RNAseq data from the validation cohort confirmed the findings.
CONCLUSIONS: High TPX2 expression may serve as a negative predictor of gemcitabine-based palliative and adjuvant chemotherapy in PDAC and could be used to inform clinical therapy decisions.
CLINICAL TRIAL REGISTRY: The clinical trial registry identifier is NCT00440167.

DOI: https://doi.org/10.1038/s41416-023-02295-x
Nature. 2023 May 03.

A phosphate-sensing organelle regulates phosphate and tissue homeostasis.

Chiwei Xu, Jun Xu, Hong-Wen Tang, Maria Ericsson, Jui-Hsia Weng, Jonathan DiRusso, Yanhui Hu, Wenzhe Ma, John M Asara, Norbert Perrimon.

Inorganic phosphate (Pi) is one of the essential molecules for life. However, little is known about intracellular Pi metabolism and signalling in animal tissues1. Following the observation that chronic Pi starvation causes hyperproliferation in the digestive epithelium of Drosophila melanogaster, we determined that Pi starvation triggers the downregulation of the Pi transporter PXo. In line with Pi starvation, PXo deficiency caused midgut hyperproliferation. Interestingly, immunostaining and ultrastructural analyses showed that PXo specifically marks non-canonical multilamellar organelles (PXo bodies). Further, by Pi imaging with a Förster resonance energy transfer (FRET)-based Pi sensor2, we found that PXo restricts cytosolic Pi levels. PXo bodies require PXo for biogenesis and undergo degradation following Pi starvation. Proteomic and lipidomic characterization of PXo bodies unveiled their distinct feature as an intracellular Pi reserve. Therefore, Pi starvation triggers PXo downregulation and PXo body degradation as a compensatory mechanism to increase cytosolic Pi. Finally, we identified connector of kinase to AP-1 (Cka), a component of the STRIPAK complex and JNK signalling3, as the mediator of PXo knockdown- or Pi starvation-induced hyperproliferation. Altogether, our study uncovers PXo bodies as a critical regulator of cytosolic Pi levels and identifies a Pi-dependent PXo-Cka-JNK signalling cascade controlling tissue homeostasis.

DOI: https://doi.org/10.1038/s41586-023-06039-y
Nat Metab. 2023 May 04.

Career pathways, part 11.

Gerta Hoxhaj, Ed Reznik.

DOI: https://doi.org/10.1038/s42255-023-00788-w
Cancer Imaging. 2023 May 02. 23(1): 43

Three-dimensional analysis of human pancreatic cancer specimens by phase-contrast based X-ray tomography - the next dimension of diagnosis.

Diana Pinkert-Leetsch, Jasper Frohn, Philipp Ströbel, Frauke Alves, Tim Salditt, Jeannine Missbach-Guentner.

   BACKGROUND: The worldwide increase of pancreatic ductal adenocarcinoma (PDAC), which still has one of the lowest survival rates, requires novel imaging tools to improve early detection and to refine diagnosis. Therefore, the aim of this study was to assess the feasibility of propagation-based phase-contrast X-ray computed tomography of already paraffin-embedded and unlabeled human pancreatic tumor tissue to achieve a detailed three-dimensional (3D) view of the tumor sample in its entirety.
METHODS: Punch biopsies of areas of particular interest were taken from paraffin blocks after initial histological analysis of hematoxylin and eosin stained tumor sections. To cover the entire 3.5 mm diameter of the punch biopsy, nine individual tomograms with overlapping regions were acquired in a synchrotron parallel beam configuration and stitched together after data reconstruction. Due to the intrinsic contrast based on electron density differences of tissue components and a voxel size of 1.3 μm achieved PDAC and its precursors were clearly identified.
RESULTS: Characteristic tissue structures for PDAC and its precursors, such as dilated pancreatic ducts, altered ductal epithelium, diffuse immune cell infiltrations, increased occurrence of tumor stroma and perineural invasion were clearly identified. Certain structures of interest were visualized in three dimensions throughout the tissue punch. Pancreatic duct ectasia of different caliber and atypical shape as well as perineural infiltration could be contiguously traced by viewing serial tomographic slices and by applying semi-automatic segmentation. Histological validation of corresponding sections confirmed the former identified PDAC features.
CONCLUSION: In conclusion, virtual 3D histology via phase-contrast X-ray tomography visualizes diagnostically relevant tissue structures of PDAC in their entirety, preserving tissue integrity in label-free, paraffin embedded tissue biopsies. In the future, this will not only enable a more comprehensive diagnosis but also a possible identification of new 3D imaging tumor markers.

Keywords:  Pancreatic cancer; Phase-contrast; Precursor lesion; Synchrotron; Virtual histology; X-ray based tomography

DOI:  https://doi.org/10.1186/s40644-023-00559-6
Nat Rev Cancer. 2023 May 02.

Untangling the mechanisms of cancer predisposition.

Giovana Tardin Torrezan.

DOI: https://doi.org/10.1038/s41568-023-00577-3
Sci Transl Med. 2023 May 03. 15(694): eabn9674

Sirtuin 6 is required for the integrated stress response and resistance to inhibition of transcriptional cyclin-dependent kinases.

Nithya Kartha, Jessica E Gianopulos, Zachary Schrank, Sarah M Cavender, Stephanie Dobersch, Bryan D Kynnap, Adrianne Wallace-Povirk, Cynthia L Wladyka, Juan F Santana, Jaeseung C Kim, Angela Yu, Caroline M Bridgwater, Kathrin Fuchs, Sarah Dysinger, Aaron E Lampano, Faiyaz Notta, David H Price, Andrew C Hsieh, Sunil R Hingorani, Sita Kugel.

Pancreatic ductal adenocarcinoma (PDAC) is classified into two key subtypes, classical and basal, with basal PDAC predicting worse survival. Using in vitro drug assays, genetic manipulation experiments, and in vivo drug studies in human patient-derived xenografts (PDXs) of PDAC, we found that basal PDACs were uniquely sensitive to transcriptional inhibition by targeting cyclin-dependent kinase 7 (CDK7) and CDK9, and this sensitivity was recapitulated in the basal subtype of breast cancer. We showed in cell lines, PDXs, and publicly available patient datasets that basal PDAC was characterized by inactivation of the integrated stress response (ISR), which leads to a higher rate of global mRNA translation. Moreover, we identified the histone deacetylase sirtuin 6 (SIRT6) as a critical regulator of a constitutively active ISR. Using expression analysis, polysome sequencing, immunofluorescence, and cycloheximide chase experiments, we found that SIRT6 regulated protein stability by binding activating transcription factor 4 (ATF4) in nuclear speckles and protecting it from proteasomal degradation. In human PDAC cell lines and organoids as well as in murine PDAC genetically engineered mouse models where SIRT6 was deleted or down-regulated, we demonstrated that SIRT6 loss both defined the basal PDAC subtype and led to reduced ATF4 protein stability and a nonfunctional ISR, causing a marked vulnerability to CDK7 and CDK9 inhibitors. Thus, we have uncovered an important mechanism regulating a stress-induced transcriptional program that may be exploited with targeted therapies in particularly aggressive PDAC.

DOI: https://doi.org/10.1126/scitranslmed.abn9674
bioRxiv. 2023 Apr 19. pii: 2023.04.19.536722. [Epub ahead of print]

A Multi-omic Analysis of the Human Lung Reveals Distinct Cell Specific Aging and Senescence Molecular Programs.

Ruben De Man, John E McDonough, Taylor S Adams, Edward P Manning, Greg Myers, Robin Vos, Laurens Ceulemans, Lieven Dupont, Bart M Vanaudenaerde, Wim A Wuyts, Ivan O Rosas, James S Hagood, Namasivayam Ambalavanan, Laura Niklason, Kirk C Hansen, Xiting Yan, Naftali Kaminski.

Age is a major risk factor for lung disease. To understand the mechanisms underlying this association, we characterized the changing cellular, genomic, transcriptional, and epigenetic landscape of lung aging using bulk and single-cell RNAseq (scRNAseq) data. Our analysis revealed age-associated gene networks that reflected hallmarks of aging, including mitochondrial dysfunction, inflammation, and cellular senescence. Cell type deconvolution revealed age-associated changes in the cellular composition of the lung: decreased alveolar epithelial cells and increased fibroblasts and endothelial cells. In the alveolar microenvironment, aging is characterized by decreased AT2B cells and reduced surfactant production, a finding that was validated by scRNAseq and IHC. We showed that a previously reported senescence signature, SenMayo, captures cells expressing canonical senescence markers. SenMayo signature also identified cell-type specific senescence-associated co-expression modules that have distinct molecular functions, including ECM regulation, cell signaling, and damage response pathways. Analysis of somatic mutations showed that burden was highest in lymphocytes and endothelial cells and was associated with high expression of senescence signature. Finally, aging and senescence gene expression modules were associated with differentially methylated regions, with inflammatory markers such as IL1B, IL6R , and TNF being significantly regulated with age. Our findings provide new insights into the mechanisms underlying lung aging and may have implications for the development of interventions to prevent or treat age-related lung diseases.

DOI: https://doi.org/10.1101/2023.04.19.536722
Sci Adv. 2023 04 28. 9(17): eadf9063

Monitoring AKT activity and targeting in live tissue and disease contexts using a real-time Akt-FRET biosensor mouse.

James R W Conway, Sean C Warren, Young-Kyung Lee, Andrew T McCulloch, Astrid Magenau, Victoria Lee, Xanthe L Metcalf, Janett Stoehr, Katharina Haigh, Lea Abdulkhalek, Cristian S Guaman, Daniel A Reed, Kendelle J Murphy, Brooke A Pereira, Pauline Mélénec, Cecilia Chambers, Sharissa L Latham, Helen Lenthall, Elissa K Deenick, Yuanqing Ma, Tri Phan, Elgene Lim, Anthony M Joshua, Stacey Walters, Shane T Grey, Yan-Chuan Shi, Lei Zhang, Herbert Herzog, David R Croucher, Andy Philp, Colinda L G J Scheele, David Herrmann, Owen J Sansom, Jennifer P Morton, Antonella Papa, Jody J Haigh, Max Nobis, Paul Timpson.

Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment of many diseases. To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models. We also show that the dynamics of AKT activation can be monitored in real time in diverse tissues, including in individual islets of the pancreas, in the brown and white adipose tissue, and in the skeletal muscle. Thus, the Akt-FRET biosensor mouse provides an important tool to study AKT dynamics in live tissue contexts and has broad preclinical applications.

DOI: https://doi.org/10.1126/sciadv.adf9063
Elife. 2023 May 02. pii: e84330. [Epub ahead of print]12

Mitochondrial protein import clogging as a mechanism of disease.

Liam P Coyne, Xiaowen Wang, Jiyao Song, Ebbing de Jong, Karin Schneider, Paul T Massa, Frank A Middleton, Thomas Becker, Xin Jie Chen.

  Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria can be disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in ADP/ATP translocase 1 (ANT1), and its yeast homolog Aac2, cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis and cell viability independent of ANT1's nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/ANT1 cause severe clogging primarily at the Translocase of the Outer Membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger ANT1 variant led to neurodegeneration and an age-dependent dominant myopathy that phenocopy ANT1-induced human disease, suggesting clogging as a mechanism of disease. More broadly, this work implies the existence of uncharacterized amino acid requirements for mitochondrial carrier proteins to avoid clogging and subsequent disease.

Keywords:  S. cerevisiae; biochemistry; chemical biology; mouse

DOI:  https://doi.org/10.7554/eLife.84330
Cell Death Differ. 2023 May 04.

Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET.

Dimitris C Kanellis, Asimina Zisi, Zdenek Skrott, Bennie Lemmens, Jaime A Espinoza, Martin Kosar, Andrea Björkman, Xuexin Li, Stefanos Arampatzis, Jirina Bartkova, Miguel Andújar-Sánchez, Oscar Fernandez-Capetillo, Martin Mistrik, Mikael S Lindström, Jiri Bartek.

Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.

DOI: https://doi.org/10.1038/s41418-023-01167-4
Trends Mol Med. 2023 Apr 28. pii: S1471-4914(23)00072-2. [Epub ahead of print]

Mitigating age-related somatic mutation burden.

Jan Vijg, Björn Schumacher, Abdulkadir Abakir, Michael Antonov, Chris Bradley, Alex Cagan, George Church, Vadim N Gladyshev, Vera Gorbunova, Alexander Y Maslov, Wolf Reik, Samim Sharifi, Yousin Suh, Kenneth Walsh.

  Genomes are inherently unstable and require constant DNA repair to maintain their genetic information. However, selective pressure has optimized repair mechanisms in somatic cells only to allow transmitting genetic information to the next generation, not to maximize sequence integrity long beyond the reproductive age. Recent studies have confirmed that somatic mutations, due to errors during genome repair and replication, accumulate in tissues and organs of humans and model organisms. Here, we describe recent advances in the quantitative analysis of somatic mutations in vivo. We also review evidence for or against a possible causal role of somatic mutations in aging. Finally, we discuss options to prevent, delay or eliminate de novo, random somatic mutations as a cause of aging.

Keywords:  aging; cancer; chromatin organization; clonal hematopoiesis; germline versus somatic genome; somatic mutations

DOI:  https://doi.org/10.1016/j.molmed.2023.04.002
Elife. 2023 May 02. pii: e82490. [Epub ahead of print]12

Physical basis of the cell size scaling laws.

Romain Rollin, Jean-François Joanny, Pierre Sens.

  Cellular growth is the result of passive physical constraints and active biological processes. Their interplay leads to the appearance of robust and ubiquitous scaling laws relating linearly cell size, dry mass, and nuclear size. Despite accumulating experimental evidence, their origin is still unclear. Here, we show that these laws can be explained quantitatively by a single model of size regulation based on three simple, yet generic, physical constraints defining altogether the Pump-Leak model. Based on quantitative estimates, we clearly map the Pump-Leak model coarse-grained parameters with the dominant cellular components. We propose that dry mass density homeostasis arises from the scaling between proteins and small osmolytes, mainly amino-acids and ions. Our model predicts this scaling to naturally fail, both at senescence when DNA and RNAs are saturated by RNA polymerases and ribosomes respectively, and at mitotic entry due to the counterion release following histone tail modifications. Based on the same physical laws, we further show that nuclear scaling results from a osmotic balance at the nuclear envelope and a large pool of metabolites, which dilutes chromatin counterions that do not scale during growth.

Keywords:  cell biology; none; physics of living systems

DOI:  https://doi.org/10.7554/eLife.82490
Science. 2023 May 05. 380(6644): 531-536

Molecular basis of translation termination at noncanonical stop codons in human mitochondria.

Martin Saurer, Marc Leibundgut, Hima Priyanka Nadimpalli, Alain Scaiola, Tanja Schönhut, Richard G Lee, Stefan J Siira, Oliver Rackham, René Dreos, Tea Lenarčič, Eva Kummer, David Gatfield, Aleksandra Filipovska, Nenad Ban.

The genetic code that specifies the identity of amino acids incorporated into proteins during protein synthesis is almost universally conserved. Mitochondrial genomes feature deviations from the standard genetic code, including the reassignment of two arginine codons to stop codons. The protein required for translation termination at these noncanonical stop codons to release the newly synthesized polypeptides is not currently known. In this study, we used gene editing and ribosomal profiling in combination with cryo-electron microscopy to establish that mitochondrial release factor 1 (mtRF1) detects noncanonical stop codons in human mitochondria by a previously unknown mechanism of codon recognition. We discovered that binding of mtRF1 to the decoding center of the ribosome stabilizes a highly unusual conformation in the messenger RNA in which the ribosomal RNA participates in specific recognition of the noncanonical stop codons.

DOI: https://doi.org/10.1126/science.adf9890
Anal Chem. 2023 Apr 26.

Selective Visualization of Tumor Cell Membranes and Tumors with a Viscosity-Sensitive Plasma Membrane Probe.

Qianhua Li, Wenlong Zhu, Shengyi Gong, Siyu Jiang, Guoqiang Feng.

Cancer is a worldwide health problem. Revealing the changes in the microenvironment after cell carcinogenesis is helpful to understand cancer and develop sensitive methods for cancer diagnosis. We developed herein a viscosity-responsive plasma membrane probe (TPA-S) that was successfully used to probe the viscosity difference between normal and tumor cell plasma membranes for the first time. The probe shows AIE properties with good water solubility, significant near-infrared (NIR) fluorescence responses to viscosity with high sensitivity, and excellent cell membrane location performance. With these features, our experiments showed that TPA-S could selectively visualize cancer cell plasma membranes, revealing that the plasma membrane of tumor cells is more viscous than that of normal cells. In addition, TPA-S was successfully applied to specifically light up tumors. Altogether, this work explored the changes of cell membrane viscosity after canceration, provided a new method for selective visualization of tumor cells, and opened up a new approach for cancer diagnosis.

DOI: https://doi.org/10.1021/acs.analchem.3c00220
Cell Chem Biol. 2023 Apr 25. pii: S2451-9456(23)00090-9. [Epub ahead of print]

CysDB: a human cysteine database based on experimental quantitative chemoproteomics.

Lisa M Boatner, Maria F Palafox, Devin K Schweppe, Keriann M Backus.

  Cysteine chemoproteomics provides proteome-wide portraits of the ligandability or potential "druggability" for thousands of cysteine residues. Consequently, these studies are facilitating resources for closing the druggability gap, namely, achieving pharmacological manipulation of ∼96% of the human proteome that remains untargeted by U.S. Food and Drug Administration (FDA) approved small molecules. Recent interactive datasets have enabled users to interface more readily with cysteine chemoproteomics datasets. However, these resources remain limited to single studies and therefore do not provide a mechanism to perform cross-study analyses. Here we report CysDB as a curated community-wide repository of human cysteine chemoproteomics data derived from nine high-coverage studies. CysDB is publicly available at https://backuslab.shinyapps.io/cysdb/ and features measures of identification for 62,888 cysteines (24% of the cysteinome), as well as annotations of functionality, druggability, disease relevance, genetic variation, and structural features. Most importantly, we have designed CysDB to incorporate new datasets to further support the continued growth of the druggable cysteinome.

Keywords:  Cysteine; chemoproteomics; covalent probes; cysteinome; database; electrophilic fragments; ligandability; multi-omics

DOI:  https://doi.org/10.1016/j.chembiol.2023.04.004
Cancer Res. 2023 May 04. pii: CAN-22-2996. [Epub ahead of print]

CellMinerCDB: NCATS is a Web-Based Portal Integrating Public Cancer Cell Line Databases for Pharmacogenomic Explorations.

William C Reinhold, Kelli Wilson, Fathi Elloumi, Katie R Bradwell, Michele Ceribelli, Sudhir Varma, Yanghsin Wang, Damien Duveau, Nikhil Menon, Jane Trepel, Xiaohu Zhang, Carleen Klumpp-Thomas, Samuel Michael, Paul Shinn, Augustin Luna, Craig Thomas, Yves Pommier.

Major advances have been made in the field of precision medicine for treating cancer. However, many open questions remain that need to be answered to realize the goal of matching every cancer patient to the most efficacious therapy. To facilitate these efforts, we have developed CellMinerCDB:NCATS (https://discover.nci.nih.gov/rsconnect/cellminercdb_ncats/), which makes available activity information for 2,675 drugs and compounds, including multiple non-oncology drugs and 1,866 drugs and compounds unique to the National Center for Advancing Translational Sciences (NCATS). CellMinerCDB:NCATS comprises 183 cancer cell lines with 72 unique to NCATS including some from previously understudied tissues of origin. Multiple forms of data from different institutes are integrated, including single and combination drug activity, DNA copy number, methylation and mutation, transcriptome, protein levels, histone acetylation and methylation, metabolites, CRISPR and miscellaneous signatures. Curation of cell lines and drug names enables cross-database (CDB) analyses. Comparison of the datasets is made possible by the overlap between cell lines and drugs across databases. Multiple univariate and multivariate analysis tools are built-in, including linear regression and LASSO. Examples have been presented here for the clinical topoisomerase I (TOP1) inhibitors topotecan and irinotecan/SN-38. This web-application provides both substantial new data and significant pharmacogenomic integration allowing exploration of interrelationships.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2996