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| Open AccessSpatial oxidation of L-plastin downmodulates actin-based functions of tumor cells
The actin-remodelling protein L-plastin promotes tumour migration and invasion. Here, the authors show that L-plastin is regulated spatially by ROS-induced thiol oxidation which inhibits its actin-bundling function and cell spreading and filopodial extension formation in tumor cells.
- Emre Balta
- , Robert Hardt
- & Yvonne Samstag
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Article
| Open AccessARID1A promotes genomic stability through protecting telomere cohesion
Cells with ARID1A mutations exhibit mitotic defects, yet show surprisingly low levels of copy number defects. Here, Zhao et al. resolve this issue by showing that ARID1A loss causes defects in telomere cohesion, which selects against gross alterations in copy number.
- Bo Zhao
- , Jianhuang Lin
- & Rugang Zhang
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Article
| Open AccessCaspase-11 signaling enhances graft-versus-host disease
An increasing number of inflammatory pathologies is associated with IL-1 production downstream of caspases 1 and 11. Here the authors show that graft-versus-host-disease (GvHD) is diminished in mice with genetic or pharmacological ablation of caspase-11, and provide mechanistic insights into the signals leading to caspase-11 activation in GvHD.
- Yanyan Lu
- , Ran Meng
- & Ben Lu
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Article
| Open AccessPatient-derived lung cancer organoids as in vitro cancer models for therapeutic screening
The clinical efficacy of standard therapy in lung cancer is limited by high level of heterogeneity. Here, the authors report patient-derived lung cancer organoids from different histological subtypes and show them to faithfully recapitulate the histology, genomics, and drug responses of the primary lung tumours.
- Minsuh Kim
- , Hyemin Mun
- & Se Jin Jang
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Article
| Open AccessCXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors
CAR T-cell therapy efficacy in solid tumors is limited by inadequate T-cell migration and/or persistence in tumour microenvironment. Here, the authors show that the activity of tumour-antigen specific CAR T cells, in multiple preclinical mouse models, can be enhanced by co-expression of two IL-8 receptors that mediate their migration into the tumor microenvironment when IL-8 production in tumor is naturally expressed or enhanced by radiation.
- Linchun Jin
- , Haipeng Tao
- & Jianping Huang
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Article
| Open AccessCell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas
The EWS-ATF1 fusion gene causes clear cell sarcoma (CCS). Here, the authors show that the downstream effects of EWS-ATF1 expression are strictly context dependent, and reveal the cell of origin for CCS to be Tppp3-expressing cells in peripheral nerves.
- Shingo Komura
- , Kenji Ito
- & Yasuhiro Yamada
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Article
| Open AccessCDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity
CDK5 is known to drive glioblastoma tumorigenicity but the downstream molecular mechanism is unknown. Here, the authors show that CDK5 activates STAT3 signalling via the nuclear import of TRIM59, which leads to the degradation of the tumour suppressor macroH2A1.
- Youzhou Sang
- , Yanxin Li
- & Haizhong Feng
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Article
| Open AccessCD36 inhibits β-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis
CD36 is a membrane glycoprotein that has been shown to have tumour promoting or suppressor function depending on tumour type. Here, the authors address CD36 function in colorectal cancer and show it acts as a tumour suppressor by inhibiting B-catenin/myc signalling, resulting in downregulation of glycolysis.
- Yuan Fang
- , Zhi-Yong Shen
- & Yi Ding
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Article
| Open AccessThe transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition
RPSAP52 is an antisense-transcribed pseudogene of HMGA2 that positively regulates HMGA2 expression. Here, the authors show that reexpression of RPSAP52 promotes tumorigenicity by facilitating IGF2BP2 binding to its mRNA targets and consequently regulates the balance of LIN28B and let-7 levels.
- Cristina Oliveira-Mateos
- , Anaís Sánchez-Castillo
- & Sonia Guil
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Article
| Open AccessGenetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers
The previous efforts to reprogramme tumour-associated macrophages (TAMs) to M1 phenotype have caused undesired side-effects. Here, the authors report targeted nanocarriers for delivering mRNA encoding M1-polarizing transcription factors to TAMs and show their efficacy in multiple mouse tumour models.
- F. Zhang
- , N. N. Parayath
- & M. T. Stephan
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Article
| Open AccessMacrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry
Tumor associated macrophages are functionally and phenotypically heterogeneous. Here the authors describe the spatial distribution of distinct macrophage populations within regions of gastric cancer and probe their associations with clinical outcomes, gene signatures and PDL1 expression.
- Yu-Kuan Huang
- , Minyu Wang
- & Alex Boussioutas
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Article
| Open AccessThe molecular origin and taxonomy of mucinous ovarian carcinoma
Whether mucinous ovarian carcinoma (MOC) arises from cells at the ovary or from metastases from other primary sites is an unanswered question. Here, Cheasley et al perform a genetic analysis of the disease, showing that MOC arises at the ovary.
- Dane Cheasley
- , Matthew J. Wakefield
- & Kylie L. Gorringe
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Article
| Open AccessLiquid biopsy tracking during sequential chemo-radiotherapy identifies distinct prognostic phenotypes in nasopharyngeal carcinoma
Liquid biopsies are emerging as a useful method for diagnosis and prognosis in cancer. Here, the authors show the prognostic value of monitoring the level of circulating Epstein-barr virus DNA throughout induction chemotherapy and chemo-radiotherapy and its potential utility for risk-adapted individualised therapy in nasopharyngeal carcinomapatients.
- Jiawei Lv
- , Yupei Chen
- & Ying Sun
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Article
| Open AccessYAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis
The molecular mechanisms driving proliferation in the pediatric brain cancer epdendymoma are poorly understood. Here the authors show that a YAP1- MAMLD1 fusion drives tumor formation in mice and show that the fusion protein can collaborate with the TEAD and NFI transcription factors.
- Kristian W. Pajtler
- , Yiju Wei
- & Daisuke Kawauchi
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Article
| Open AccessSingle-cell transcriptomics reveals multi-step adaptations to endocrine therapy
The development of resistance to endocrine therapy is a significant, clinical problem in breast cancer. Here, the authors identify a rare subpopulation of cells that drive resistance following transcriptional reprogramming.
- Sung Pil Hong
- , Thalia E. Chan
- & Luca Magnani
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Article
| Open AccessTumor-reprogrammed resident T cells resist radiation to control tumors
Lymphocytes are considered one of the most radiosensitive cell types in the body. Here the authors show that unlike circulating lymphocytes, tumor-infiltrating T cells survive therapeutic doses of irradiation, remaining functional and contributing to radiotherapy induced anti-tumor immunity.
- Ainhoa Arina
- , Michael Beckett
- & Ralph R. Weichselbaum
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Article
| Open AccessDistinct methylation levels of mature microRNAs in gastrointestinal cancers
In cancer it is assumed that microRNAs recognise and regulate their targets uniformly. Here, the authors show that in gastrointestinal cancers methylation of microRNAs may impact their stability, and that levels of microRNA methylation are distinct in pancreatic cancer patients compared to healthy controls with potential diagnostic implications.
- Masamitsu Konno
- , Jun Koseki
- & Hideshi Ishii
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Article
| Open AccessCSL controls telomere maintenance and genome stability in human dermal fibroblasts
Conversion of dermal fibroblasts into Cancer Associated Fibroblasts (CAFs) can play an important role in keratinocyte tumour development. Here the authors reveal that CSL plays a role in maintenance of telomeres and genomic integrity in both dermal fibroblasts and CAFs.
- Giulia Bottoni
- , Atul Katarkar
- & G. Paolo Dotto
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Review Article
| Open AccessEmerging epigenomic landscapes of pancreatic cancer in the era of precision medicine
In pancreatic cancer, the epigenomic landscape can strongly impact the disease phenotype. Here, the authors discuss recent advances in our understanding of pancreatic cancer epigenomics, and how this knowledge can integrate with precision medicine approaches in this lethal disease.
- Gwen Lomberk
- , Nelson Dusetti
- & Raul Urrutia
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Article
| Open AccessBlood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy
Glioma therapy with checkpoint inhibitors has limited blood–brain barrier (BBB) penetration and therapeutic effects. Here, the authors develop nanopolymer-conjugated checkpoint inhibitors and show their trans-BBB delivery and anti-glioma efficacy.
- Anna Galstyan
- , Janet L. Markman
- & Julia Y. Ljubimova
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Article
| Open AccessGREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling
The mechanisms promoting hepatoblastoma (HB) progression through Wnt/β-catenin signaling are unclear. Here, the authors show that the Wnt/ β-catenin axis induces GREB1 expression and nuclear localization, and suppresses TGFβ pathway, and propose GREB1 as a therapeutic target in HB.
- Shinji Matsumoto
- , Taku Yamamichi
- & Akira Kikuchi
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Article
| Open AccessA next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control
Interleukin-2 (IL-2) based cancer therapy is limited by severe toxicity and strong Treg amplification at the therapeutic dosage. Here, the authors develop a recombinant IL-2 immunocytokine which is comprised of a tumor-targeting antibody fused to a super mutant IL-2 and show in mouse models that this next-generation IL2 has reduced toxicity and enhanced antitumor activity.
- Zhichen Sun
- , Zhenhua Ren
- & Hua Peng
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Article
| Open AccessPriming mobilization of hair follicle stem cells triggers permanent loss of regeneration after alkylating chemotherapy
Hair follicles (HFs) are sensitive to chemotherapy but recover from quiescent HF stem cells, although sometimes chemotherapy results in permanent loss. Here, Kim et al. establish a model of permanent chemotherapy-induced alopecia to uncover the underlying mechanisms depleting human HF stem cells.
- Jin Yong Kim
- , Jungyoon Ohn
- & Ohsang Kwon
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Article
| Open AccessLiquid biopsy-based single-cell metabolic phenotyping of lung cancer patients for informative diagnostics
Non-invasive methods to predict treatment response are urgently needed. Here in lung cancer, the authors develop a single-cell on-chip cytometry method to metabolically phenotype disseminated tumor cells, revealing metabolic heterogeneity and predictors of therapy response and survival.
- Ziming Li
- , Zhuo Wang
- & Qihui Shi
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Comment
| Open AccessMicroenvironment meets lineage complexity in junctional tumorigenesis
Using a sensitizing genetic model, Moon and colleagues provide compelling data for a determinant role of microenvironment in tumorigenesis, and lend support to the notion that such influences can be pharmacologically dampened to reduce the onset of cancers.
- Wa Xian
- & Frank McKeon
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Article
| Open AccessRebalancing of actomyosin contractility enables mammary tumor formation upon loss of E-cadherin
E-cadherin is a well-known tumor suppressor albeit loss of E-cadherin alone is insufficient to induce mammary tumorigenesis. Here the authors report that epithelial cells that have lost E-cadherin can survive by extruding to the basal lamina but require rebalancing of actomyosin contractility to drive tumor development.
- Koen Schipper
- , Danielle Seinstra
- & Jos Jonkers
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Article
| Open AccessSingle-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer
The benefit of combined CDK4/6 and anti-HER2 therapy in breast cancer is limited due to acquired resistance. Here, the authors perform single-cell analysis and show an immature myeloid cell population to infiltrate resistant tumors, and that combined cabozantinib and checkpoint therapy overcome this resistance with a sustained efficacy.
- Qingfei Wang
- , Ian H. Guldner
- & Siyuan Zhang
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Article
| Open AccesshCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy
Acute myeloid leukemia cells are often resistant to radiotherapy and chemotherapy. Here, the authors suggest that hCINAP contributes to the resistance of acute myeloid leukemia cells by regulating SUMOylation of Nucleophosmin during the DNA-damage response.
- Ruidan Xu
- , Shuyu Yu
- & Xiaofeng Zheng
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Article
| Open AccessGenomic landscape and chronological reconstruction of driver events in multiple myeloma
Multiple myeloma evolves continuously. Here the authors chronologically reconstruct driver events in multiple myeloma, noting a limited repertoire of initiating driver events that shape the evolutionary trajectory of the disease.
- Francesco Maura
- , Niccoló Bolli
- & Peter J. Campbell
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Article
| Open AccessTumor exosome-based nanoparticles are efficient drug carriers for chemotherapy
The generation of biomimetic nanoparticles that retain the integrity of proteins has been a challenge. Here, the authors generate biomimetic nanoparticles that are exocytosed from tumour cells and show their therapeutic potential in targeting tumours and cancer stem cells in multiple mouse models.
- Tuying Yong
- , Xiaoqiong Zhang
- & Xiangliang Yang
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Article
| Open AccessPPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma
Mutations in the Protein Phosphatase PPM1D are oncogenic in certain cancers including diffuse intrinsic pontine glioma (DIPG). Here, the authors show that PPM1D mutations in DIPG induce the silencing of the nicotinic acid phosphoribosyltransferase gene and display synthetic lethality with nicotinamide phosphoribosyltransferase inhibitors.
- Nathan R. Fons
- , Ranjini K. Sundaram
- & Ranjit S. Bindra
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Article
| Open AccessB1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis
Promyelocytic leukemia protein (PML) is the scaffolding protein that organizes PML nuclear bodies. Here the authors determine the crystal structure of a PML B1-box multimer and characterise the oligomerisation behaviour of the PML RBCC construct and show that disrupting B1-B1 interactions precludes promyelocytic leukemia leukemogenesis in transgenic mice.
- Yuwen Li
- , Xiaodan Ma
- & Guoyu Meng
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Article
| Open AccessThe Eleanor ncRNAs activate the topological domain of the ESR1 locus to balance against apoptosis
Long term estrogen deprivation can result in apoptosis in breast cancer cells. Here, the authors show that this apoptosis is induced by the long-range chromatin interaction of loci containing the ESR1 and FOXO3 genes, resulting in FOXO3-mediated apoptosis.
- Mohamed Osama Ali Abdalla
- , Tatsuro Yamamoto
- & Noriko Saitoh
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Article
| Open AccessMetabolic landscape of the tumor microenvironment at single cell resolution
Each cell type in the tumour microenvironment has unique metabolic demands enabling specific functions. Here the authors use published single-cell RNA-seq data and develop a computational framework to better understand the heterogeneity of tumour metabolism, highlighting the discordance between results obtained from single cells and bulk tumours.
- Zhengtao Xiao
- , Ziwei Dai
- & Jason W. Locasale
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Article
| Open AccessGenotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis
It is known that genotoxic stress induces high levels of ROS and deplete cellular glutathione stores. Here, Cao et al. uncover a β-catenin-dependent TCF/LEF-independent mechanism that promotes histone-mediated transcriptional activation of glutathione synthesis.
- Lixue Cao
- , Geyan Wu
- & Jun Li
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Article
| Open AccessTumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity
The anti-tumour immune response greatly depends on the number of tumour neoantigens. Here the authors show in mouse models that a therapeutic strategy aimed at increasing the number of neoantigens via downregulating TAP, an antigen processing associated protein, enhances anti-tumour immunity and the efficacy of immunotherapy.
- Greta Garrido
- , Brett Schrand
- & Eli Gilboa
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Article
| Open AccessSyringeable immunotherapeutic nanogel reshapes tumor microenvironment and prevents tumor metastasis and recurrence
The limited efficacy of current immunotherapy suggests low antigen-specific T cells and immunosuppressive factors in tumor microenvironment (TME). Here, the authors develop a syringeable immunomodulatory multi-domain nanogel that can reprogram the TME and induce enhanced cancer immunotherapy.
- Chanyoung Song
- , Hathaichanok Phuengkham
- & Yong Taik Lim
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Article
| Open AccessPAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma
Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in activating genes associated with metabolic pathways.
- Melusine Bleu
- , Swann Gaulis
- & Giorgio G. Galli
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Article
| Open AccessIntegrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids
The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Here, Alcala and colleagues present a multi-omics analysis of these tumours, revealing distinct molecular and prognostic subgroups.
- N. Alcala
- , N. Leblay
- & L. Fernandez-Cuesta
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Article
| Open AccessComprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients
Activating oncogenic mutations in KRAS and NRAS are common in colorectal cancer, which is a heterogenous disease. Here, the authors show that the RAS mutation spectrum is markedly different between colon and rectal cancer, and also different based on age of diagnosis and microsatellite instability.
- Ilya G. Serebriiskii
- , Caitlin Connelly
- & Joshua E. Meyer
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Article
| Open AccessMitogenic and progenitor gene programmes in single pilocytic astrocytoma cells
Pilocytic astrocytoma is a low-grade pediatric glioma, characterized by a single BRAF rearrangement. Here, Reitman and colleagues use single-cell RNA sequencing to reveal molecular hallmarks of the disease that might be targeted therapeutically.
- Zachary J. Reitman
- , Brenton R. Paolella
- & Rameen Beroukhim
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Article
| Open AccessInterplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis
The Anaphase Promoting Complex adaptor protein Cdh1 tightly controls cell cycle progression to restrain tumorigenesis but the mechanism is not completely known. Here, the authors show that reciprocal inhibition between Cdh1 and the c-Src signaling pathway regulate breast cancer tumorigenesis.
- Tao Han
- , Shulong Jiang
- & Lixin Wan
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Article
| Open AccessN-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals
O-glycosylation of neuropilin-1 is involved in cancer migration and invasion. Here, the authors show that defects in N-glycosylation of two neuropilin-1 splice variants enhance the co-internalisation of Met, it’s interaction with β1-integrin, and subsequent constitutive activation of FAK/p130Cas signalling in endosomes to promote colorectal cancer metastasis.
- Xiuping Huang
- , Qing Ye
- & Qing-Bai She
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Article
| Open AccessDeep multiomics profiling of brain tumors identifies signaling networks downstream of cancer driver genes
Multi-omic profiling is a powerful approach to dissecting molecular mechanisms in disease. Here the authors generate whole proteome, phosphoproteome and transcriptome profiles from two mouse models of high-grade glioma driven by different oncogenes, and validate identified master regulators with a CRISPR screen.
- Hong Wang
- , Alexander K. Diaz
- & Junmin Peng
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Article
| Open AccessCancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis
DICER is involved in the processing of miRNAs, where the RNase IIIa and IIIb domains are thought to cut the 3p and 5p hairpin arms, respectively. Here, in endometrial cancer, the authors identify an RNase IIIa mutation, which phenocopies mutations in the RNase IIIb domain.
- Jeffrey Vedanayagam
- , Walid K. Chatila
- & Eric C. Lai
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Article
| Open AccessA general approach for detecting expressed mutations in AML cells using single cell RNA-sequencing
The advent of single-cell RNA sequencing has revealed significant transcriptional heterogeneity in cancer, but its relationship to genomic heterogeneity remains unclear. Focusing on acute myeloid leukemia samples, the authors describe a general approach for linking mutation-containing cells to their transcriptional phenotypes using single-cell RNA sequencing data.
- Allegra A. Petti
- , Stephen R. Williams
- & Timothy J. Ley
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Article
| Open AccessAutophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3 expression
Cancer cells can use autophagy as a mechanism of surviving from external stresses. Here, the authors show that Pfkfb3, a glycolytic gene, is expressed in metastatic breast cancer cells but not in dormant cells that demonstrate features of autophagy.
- Alyssa La Belle Flynn
- , Benjamin C. Calhoun
- & William P. Schiemann
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Article
| Open AccessFlavonoid intake is associated with lower mortality in the Danish Diet Cancer and Health Cohort
The studies showing health benefits of flavonoids and their impact on cancer mortality are incomplete. Here, the authors perform a prospective cohort study in Danish participants and demonstrate an inverse association between regular flavonoid intake and both cardiovascular and cancer related mortality.
- Nicola P. Bondonno
- , Frederik Dalgaard
- & Jonathan M. Hodgson
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Article
| Open AccessCAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.
- Claire Vennin
- , Pauline Mélénec
- & Paul Timpson
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