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On page 1 showing 1 ~ 16 papers out of 16 papers

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

  • Jo Lynne Rokita‎ et al.
  • Cell reports‎
  • 2019‎

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.


Bile acids target mitofusin 2 to differentially regulate innate immunity in physiological versus cholestatic conditions.

  • Yuan Che‎ et al.
  • Cell reports‎
  • 2023‎

Systemic metabolites serving as danger-associated molecular patterns play crucial roles in modulating the development, differentiation, and activity of innate immune cells. Yet, it is unclear how innate immune cells detect systemic metabolites for signal transmission. Here, we show that bile acids function as endogenous mitofusin 2 (MFN2) ligands and differentially modulate innate immune response to bacterial infection under cholestatic and physiological conditions. Bile acids at high concentrations promote mitochondrial tethering to the endoplasmic reticulum (ER), leading to calcium overload in the mitochondrion, which activates NLRP3 inflammasome and pyroptosis. By contrast, at physiologically relevant low concentrations, bile acids promote mitochondrial fusion, leading to enhanced oxidative phosphorylation and thereby strengthening infiltrated macrophages mediated phagocytotic clearance of bacteria. These findings support that bile acids, as endogenous activators of MFN2, are vital for tuning innate immune responses against infections, representing a causal link that connects systemic metabolism with mitochondrial dynamics in shaping innate immunity.


Dipeptidylpeptidase 4 promotes survival and stemness of acute myeloid leukemia stem cells.

  • Chen Wang‎ et al.
  • Cell reports‎
  • 2023‎

Leukemic-stem-cell-specific targeting may improve the survival of patients with acute myeloid leukemia (AML) by avoiding the ablative effects of standard regimens on normal hematopoiesis. Herein, we perform an unbiased screening of compounds targeting cell surface proteins and identify clinically used DPP4 inhibitors as strong suppressors of AML development in both murine AML models and primary human AML cells xenograft model. We find in retrovirus-induced AML mouse models that DPP4-deficient AML cell-transplanted mice exhibit delay and reversal of AML development, whereas deletion of DPP4 has no significant effect on normal hematopoiesis. DPP4 activates and sustains survival of AML stem cells that are critical for AML development in both human and animal models via binding with Src kinase and activation of nuclear factor κB (NF-κB) signaling. Thus, inhibition of DPP4 is a potential therapeutic strategy against AML development through suppression of survival and stemness of AML cells.


In vivo SILAC-based proteomics reveals phosphoproteome changes during mouse skin carcinogenesis.

  • Sara Zanivan‎ et al.
  • Cell reports‎
  • 2013‎

Cancer progresses through distinct stages, and mouse models recapitulating traits of this progression are frequently used to explore genetic, morphological, and pharmacological aspects of tumor development. To complement genomic investigations of this process, we here quantify phosphoproteomic changes in skin cancer development using the SILAC mouse technology coupled to high-resolution mass spectrometry. We distill protein expression signatures from our data that distinguish between skin cancer stages. A distinct phosphoproteome of the two stages of cancer progression is identified that correlates with perturbed cell growth and implicates cell adhesion as a major driver of malignancy. Importantly, integrated analysis of phosphoproteomic data and prediction of kinase activity revealed PAK4-PKC/SRC network to be highly deregulated in SCC but not in papilloma. This detailed molecular picture, both at the proteome and phosphoproteome level, will prove useful for the study of mechanisms of tumor progression.


A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence.

  • Camila Ferreira de Souza‎ et al.
  • Cell reports‎
  • 2018‎

Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression.


Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway.

  • Jian Carrot-Zhang‎ et al.
  • Cell reports‎
  • 2021‎

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.


Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas.

  • Joshua D Campbell‎ et al.
  • Cell reports‎
  • 2018‎

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.


The Cyclopeptide Astin C Specifically Inhibits the Innate Immune CDN Sensor STING.

  • Senlin Li‎ et al.
  • Cell reports‎
  • 2018‎

cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1-/- BMDM cells and in Trex1-/- mouse autoimmune disease model. Mechanistically, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases.


Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation.

  • Marie-Claude Gingras‎ et al.
  • Cell reports‎
  • 2016‎

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.


Integrated Molecular Characterization of Testicular Germ Cell Tumors.

  • Hui Shen‎ et al.
  • Cell reports‎
  • 2018‎

We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.


HERC5-catalyzed ISGylation potentiates cGAS-mediated innate immunity.

  • Lei Chu‎ et al.
  • Cell reports‎
  • 2024‎

The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential to elicit type I interferon cascade response; thus, the activity of cGAS must be strictly regulated to boost the antiviral innate immunity. Here, we report that cGAS is responsible for the DNA-induced ISG15 conjugation system. The E3 HERC5 catalyzes the ISGylation of cytoplasmic cGAS at lysine 21, 187, 219, and 458, whereas Ubl carboxy-terminal hydrolase 18 removes the ISGylation of cGAS. The interaction of cGAS and HERC5 depends on the cGAS C-terminal domain and the RRC1-4 and RRC1-5 domains of HERC5. Mechanically, HERC5-catalyzed ISGylation promotes DNA-induced cGAS oligomerization and enhances cGAS enzymatic activity. Deficiency of ISGylation attenuates the downstream inflammatory gene expression induced by the cGAS-STING axis and the antiviral ability in mouse and human cells. Mice deficient in Isg15 or Herc6 are more vulnerable to herpes simplex virus 1 infection. Collectively, our study shows a positive feedback regulation of the cGAS-mediated innate immune pathway by ISGylation.


The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.

  • Christopher J Ricketts‎ et al.
  • Cell reports‎
  • 2018‎

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.


Nuclear cGAS Functions Non-canonically to Enhance Antiviral Immunity via Recruiting Methyltransferase Prmt5.

  • Shufang Cui‎ et al.
  • Cell reports‎
  • 2020‎

Cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS), upon sensing cytosolic DNA, catalyzes the production of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which activates STING-TBK1-IRF3 signaling. cGAS is also present in the nucleus, but the relevant nuclear function or mechanism remains largely unknown. Here, we report that nuclear cGAS is indispensable for inducing cytokines and chemokines triggered by RNA/DNA viruses. Unexpectedly, the DNA-binding/nucleotidyltransferase activity of cGAS is dispensable for RNA-virus-induced genes expression. cGAS deficiency does not affect the phosphorylation, dimerization, or nuclear translocation of IRF3 induced by double-stranded RNA (dsRNA). Mechanistically, nuclear-localized cGAS interacts with protein arginine methyltransferase 5 (Prmt5), which catalyzes the symmetric dimethylation of histone H3 arginine 2 at Ifnb and Ifna4 promoters, thus facilitating the access of IRF3. Deficiency of Prmt5 or disrupting its catalytic activity suppresses the production of type I interferons (IFNs), impairing the host defenses against RNA/DNA virus infections. Taken together, our study uncovers a non-canonical function of nuclear-localized cGAS in innate immunity via regulating histone arginine modification.


Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.

  • Fengju Chen‎ et al.
  • Cell reports‎
  • 2016‎

On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.


Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.

  • Theo A Knijnenburg‎ et al.
  • Cell reports‎
  • 2018‎

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.


Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling.

  • Zhaowei Tu‎ et al.
  • Cell reports‎
  • 2022‎

CHD8 is an ATP-dependent chromatin-remodeling factor whose monoallelic mutation defines a subtype of autism spectrum disorders (ASDs). Previous work found that CHD8 is required for the maintenance of hematopoiesis by integrating ATM-P53-mediated survival of hematopoietic stem/progenitor cells (HSPCs). Here, by using Chd8F/FMx1-Cre combined with a Trp53F/F mouse model that suppresses apoptosis of Chd8-/- HSPCs, we identify CHD8 as an essential regulator of erythroid differentiation. Chd8-/-P53-/- mice exhibited severe anemia conforming to congenital dyserythropoietic anemia (CDA) phenotypes. Loss of CHD8 leads to drastically decreased numbers of orthochromatic erythroblasts and increased binucleated and multinucleated basophilic erythroblasts with a cytokinesis failure in erythroblasts. CHD8 binds directly to the gene bodies of multiple Rho GTPase signaling genes in erythroblasts, and loss of CHD8 results in their dysregulated expression, leading to decreased RhoA and increased Rac1 and Cdc42 activities. Our study shows that autism-associated CHD8 is essential for erythroblast cytokinesis.


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