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| Open AccessTissue-location-specific transcription programs drive tumor dependencies in colon cancer
Cancers of the same tissue type are characterized with different molecular features depending on anatomical location. Here, the authors show that proximal and distal colon stem cells have distinct transcriptional programs mediated by the transcription factor CDX2, with differential roles in colon cancers based on anatomical location.
- Lijing Yang
- , Lei Tu
- & Hariharan Easwaran
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Article
| Open AccessLeukemic stem cells activate lineage inappropriate signalling pathways to promote their growth
In Acute Myeloid Leukemia a population of quiescent leukemic stem cells (LSCs) evade chemotherapy and initiate relapse, but what makes them grow again is unknown. Here, the authors show (i) that LSCs hijack ectopic signaling pathways to kick-start their growth and (ii) that growth can be blocked with repurposed drugs in t(8;21) AML sub-type.
- Sophie G. Kellaway
- , Sandeep Potluri
- & Constanze Bonifer
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Article
| Open AccessAggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer
The role of aggresomes in tumorigenesis and cancer progression remains to be explored. Here, the authors perform multi-omics and reveal that aggresome formation supports ovarian cancer stem cell properties via OTUD1 and ASK1/JNK signalling activation.
- Yurou Chen
- , Yulong Qiang
- & Feng Li
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Article
| Open AccessCaloric restriction leads to druggable LSD1-dependent cancer stem cells expansion
Caloric restriction (CR) has been demonstrated to have a role in tumour growth and therapy response but its effects on cancer stem cells are less known. Here, in Acute Promyelocytic Leukemia, the authors show that despite initial anti-tumour effect, CR drives the selection of leukaemia-initiating cells resulting in relapse which could be prevented by ablation of LSD1.
- Rani Pallavi
- , Elena Gatti
- & Pier Giuseppe Pelicci
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Article
| Open AccessA telomere-targeting drug depletes cancer initiating cells and promotes anti-tumor immunity in small cell lung cancer
Therapeutic options for small cell lung cancer (SCLC) are limited. Here the authors show that a telomere-targeting drug, 6-Thio-2’-deoxyguanosine, inhibits growth of SCLC tumors by inducing telomere dysfunction preferentially in cancer initiating cells and promoting anti-tumor immune responses.
- Buse Eglenen-Polat
- , Ryan R. Kowash
- & Esra A. Akbay
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Article
| Open AccessActivating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease
The inability of tyrosine kinase inhibitors to eliminate quiescent leukaemic stem cells (LSC) in chromic myeloid leukaemia (CML) results in recurrence. Here, the authors identify a reliance of CML LSCs on low P53 expression for self-renewal and therapeutically target this by combining an MDM2 inhibitor with TKI in preclinical models of CML.
- Mary T. Scott
- , Wei Liu
- & David Vetrie
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Article
| Open AccessStabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells
Post-translational modifications including protein sumoylation is under specific regulation in glioma stem cells (GSCs). Here, the authors show that Pin1 is deubiquitinated and stabilized by USP34, which in turn promotes isomerization of Ubc9, leading to SUMO1-modified global hypersumoylation to maintain the tumorigenic capacity of GSCs.
- Qiuhong Zhu
- , Panpan Liang
- & Wenchao Zhou
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Article
| Open AccessSPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma
In liver cancer, the presence of tumour-initiating cell subsets are associated with poorer prognosis and chemotherapy resistance in liver cancer. Here, the authors show that upon treatment with 5-FU or cisplatin, this subset releases SPINK1 which binds EGFR, activating the ERK-CDK4/6-E2F2 signaling cascade and resulting in chemoresistance.
- Ki-Fong Man
- , Lei Zhou
- & Stephanie Ma
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Article
| Open AccessID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer
Inhibitor of differentiation 1 (ID1) has been described as a cancer-promoting factor and also involved in the formation of an immunosuppressive tumor microenvironment. Here the authors report that ID1-expressing tumor associated macrophages favor colorectal cancer progression by promoting cancer cell stemness and CD8+ T cell exclusion.
- Shuang Shang
- , Chen Yang
- & Fang Hua
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Article
| Open AccessLncRNA INHEG promotes glioma stem cell maintenance and tumorigenicity through regulating rRNA 2’-O-methylation
Long noncoding RNAs (lncRNAs) may contribute to cancer progression. Here the authors show that LncRNA INHEG modulates rRNA 2’-O-methylation and facilitates mRNA translation to promote glioma stem cell renewal and growth.
- Lihui Liu
- , Ziyang Liu
- & Runsheng Chen
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Article
| Open AccessBroad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma
Acquired resistance to cancer therapies can develop due to kinase rewiring. Here, using a broad-spectrum chemical probe, the authors perform kinome screening and identify CDK6-mediated accumulation of cancer stem cells as a driver of lenvatinib (multitargeted tyrosine kinase inhibitor) resistance in hepatocellular carcinoma.
- Carmen Oi Ning Leung
- , Yang Yang
- & Terence Kin Wah Lee
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Article
| Open AccessDistinct and targetable role of calcium-sensing receptor in leukaemia
Several parameters in the bone marrow (BM) niche regulate leukaemic stem cell status and disease progression. Here, the authors show that calcium-sensing receptor affects the location of acute myeloid leukaemia (AML) cells in the BM niche which influences self-renewal of leukaemic stem cells and AML development
- Raquel S. Pereira
- , Rahul Kumar
- & Daniela S. Krause
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Article
| Open AccessSCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity
Cancer stem cells are known to promote hepatocellular carcinoma (HCC) initiation, metastasis and resistance. Here, the authors identify SCARB2 as a driver of tumour-initiating cells via enhanced MYC activity and evaluate the efficacy of targeting this interaction using an FDA approved drug, Polymyxin-B, in preclinical models of HCC.
- Feng Wang
- , Yang Gao
- & Ke Li
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Article
| Open AccessKMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics
The molecular mechanisms involved in the maintenance of pancreatic cancer stem cells (PCSCs) characteristics are unclear. Here, the authors identify the histone methyltransferase KMT2A as a binding partner of the PHF5A-PHF14-HMG20A-RAI1 protein subcomplex and an epigenetic regulator of the PCSCs characteristics and show the therapeutic potential of targeting this axis in pancreatic cancer.
- Mai Abdel Mouti
- , Siwei Deng
- & Siim Pauklin
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Article
| Open AccessAcquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis
The molecular mechanisms underlying the transformation of Chronic Myeloid Leukaemia (CML) from chronic phase (CP) to blast crisis (BC) are not completely elucidated. Here, the authors show that acquired miR-142 deficiency drives CML BC by regulating mitochondrial metabolism and is a potential therapeutic target to prevent BC in CML murine models.
- Bin Zhang
- , Dandan Zhao
- & Guido Marcucci
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Article
| Open AccessEpigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics
The role of histone deacetylases (HDACs) in glioblastoma brain tumour stem cells (BTSCs) remains to be explored. Here, pharmacological inhibition and genetic loss of function approaches show that HDAC2 leads to the maintenance of BTSC growth and self-renewal through its association with the components of the TGF-β signalling pathway.
- Ravinder K. Bahia
- , Xiaoguang Hao
- & Samuel Weiss
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Article
| Open AccessMutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin
Dynamic proteolipid nanoassemblies at the plasma membrane of colonocytes serve as Wnt signaling hubs. Here, the authors find a role for mutant APC in colorectal cancer in the dysregulation of plasma membrane sterol homeostasis.
- Alfredo Erazo-Oliveras
- , Mónica Muñoz-Vega
- & Robert S. Chapkin
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Article
| Open AccessmacroH2A2 antagonizes epigenetic programs of stemness in glioblastoma
Self-renewing cells play an important role in initiation, progression, and therapy resistance in glioblastoma. Here, the authors identify histone variant macroH2A2 as a regulator of chromatin organisation resulting in the suppression of transcriptional programs of self-renewal in glioblastoma.
- Ana Nikolic
- , Francesca Maule
- & Marco Gallo
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Article
| Open AccessADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer
Resistance to 5-fluorouracil and cisplatin (5FU + CDDP) presents a major issue in patients with gastric cancer. Here, the authors establish 5FU + CDDP resistant intestinal gastric cancer patient-derived organoids and identify JAK/STAT-ADAR1 altered lipid metabolism as a regulator of chemoresistance.
- Tin-Lok Wong
- , Jia-Jian Loh
- & Stephanie Ma
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Article
| Open AccessKK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer
The presence of breast cancer stem cells is associated with therapy resistance in patients with triple-negative breast cancer (TNBC). Here, the authors identify KK-LC-1-mediated YAP signaling as a driver of TNBC stemness and develop a therapeutic molecule to target this axis in preclinical models of TNBC.
- Jiawen Bu
- , Yixiao Zhang
- & Caigang Liu
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Article
| Open AccessSema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma
Wnt signaling is dysregulated in glioblastoma (GBM). Here the authors show that Semaphorin 3C drives Wnt signaling through Rac1-dependent β-catenin nuclear accumulation and that dual blockade of Semaphorin 3C and Wnt pathway reduces the growth of GBM in vivo.
- Jing Hao
- , Xiangzi Han
- & Jennifer S. Yu
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Article
| Open AccessInflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis
Age related accumulation of adipocytes in the bone marrow could alter normal and leukemic haematopoiesis. Here, in fatty bone marrow (FBM) preclinical models, the authors show that inflammatory cytokines increased in the FBM, such as IL-6, promote DNMT3a driven clonal hematopoiesis.
- N. Zioni
- , A. Akhiad Bercovich
- & Liran I. Shlush
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Article
| Open AccessSpontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas
It remains unclear how spontaneous Pancreatic Ductal Adenocarcinoma (PDAC) tumors escape Yap dependency. Here, the authors show that lineage plasticity promotes spontaneous relapse following YAP ablation and reveal key transcriptional drivers that overcome YAP addiction in PDAC.
- Shigekazu Murakami
- , Shannon M. White
- & Chunling Yi
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Article
| Open AccessRecapitulating thyroid cancer histotypes through engineering embryonic stem cells
Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. Here, the authors show the ability of human embryonic stem cells (hESCs) to recapitulate the different TC histotypes upon specific genomic alterations delivered by CRISPR-Cas9 and identify KISS1R and TIMP1 targeting as a therapeutic adjuvant option for undifferentiated TCs.
- Veronica Veschi
- , Alice Turdo
- & Giorgio Stassi
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Article
| Open AccessmcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs
Metabolic reprogramming plays vital roles in tumorigenesis. Here, Chen et al. reveal that mitochondria-encoded mcPGK1 drives the mitochondrial translocation of PGK1, promoting liver tumorigenesis and TIC self-renewal by switching energy production from OXPHOS to glycolysis.
- Zhenzhen Chen
- , Qiankun He
- & Pingping Zhu
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Article
| Open AccessSmarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma
Clinical management of pancreatic cancer remains challenging. Here, the authors suggest SMARCD3 as a potential epigenetic dependency establishing the metabolic landscape in aggressive pancreatic cancer cells and as a potential therapeutic target in pancreatic cancer.
- L. Paige Ferguson
- , Jovylyn Gatchalian
- & Tannishtha Reya
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Article
| Open AccessNiche stiffness sustains cancer stemness via TAZ and NANOG phase separation
Stromal cells in the tumour microenvironment are reported to regulate cancer stemness via biomechanical signals. Here the authors show that TAZ activated by biomechanical cues enhanced cancer stem cell properties via phase separation with Nanog.
- Xinwei Liu
- , Yingying Ye
- & Qiyi Zhao
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Article
| Open AccessCharacterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma
MYC amplification is an independent prognostic factor for the most aggressive subgroup (Group 3) of pediatric medulloblastoma (G3 MB). Here, the authors highlight the role of the RNA-binding protein, Musashi-1 (MSI1) in G3 MB and identify MSI1-bound targets sharing MYC associated pathways.
- Michelle M. Kameda-Smith
- , Helen Zhu
- & Sheila K. Singh
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Article
| Open AccessReplication collisions induced by de-repressed S-phase transcription are connected with malignant transformation of adult stem cells
Suppression of transcription in S-phase is crucial to prevent genome instability. Zhang et al demonstrate that increase of H4K20me1 due to loss of Kmt5b cause genome instability in muscle stem cells, resulting in stem cell senescence but rhabdomyosarcoma formation when p53 is inactivated.
- Ting Zhang
- , Carsten Künne
- & Thomas Braun
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Article
| Open AccessHSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia
Acute myeloid leukaemia (AML) is maintained by self-renewing leukemic stem cells. Here the authors show that Heat Shock Transcription Factor 1 (HSF1) is specifically required for the maintenance of AML stem cells, while sparing steady-state and stressed haematopoiesis and that pharmacologically targeting HSF1 may have broad anti-leukemic effects.
- Qianze Dong
- , Yan Xiu
- & Chen Zhao
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Article
| Open AccessAngiocrine extracellular vesicles impose mesenchymal reprogramming upon proneural glioma stem cells
Glioma stem-like cells (GSCs) exhibit plasticity during proneural-to-mesenchymal transition. Here the authors show that extracellular vesicles from endothelial cells can promote this transition of GSCs through activation of MMPs and NFkB, and inactivation of NOTCH.
- Lata Adnani
- , Jordan Kassouf
- & Janusz Rak
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Article
| Open AccessA slow-cycling/quiescent cells subpopulation is involved in glioma invasiveness
Quiescent cancer stem cells have been particularly associated to chemoresistance. Here, the authors show that a slowcycling subpopulation in high-grade glioma patients can invade the brain to promote tumourigenesis.
- Francesco Antonica
- , Lucia Santomaso
- & Luca Tiberi
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Article
| Open AccessCircular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands
Glioblastoma (GBM) is a highly aggressive brain tumor, frequently resistant to therapies, including natural killer (NK) cell based immunotherapy. Here, the authors show that the circular RNA EZH2 is highly expressed in GBM and encodes the peptide EZH2-92aa, whose expression is associated with inhibition of NK cell cytotoxicity.
- Jian Zhong
- , Xuesong Yang
- & Nu Zhang
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Article
| Open AccessClub cells employ regeneration mechanisms during lung tumorigenesis
Lung adenocarcinoma is a highly plastic tumour type. Here, the authors use single cell RNA sequencing to show that Club cells use regeneration mechanisms to develop tumours after an epigenetic switch towards an AT2-like phenotype shown by methylome analysis.
- Yuanyuan Chen
- , Reka Toth
- & Rocio Sotillo
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Article
| Open AccessMinimally invasive detection of cancer using metabolic changes in tumor-associated natural killer cells with Oncoimmune probes
NK cells can be affected by tumour cells and this difference could be utilised as a cancer diagnostic. Here the authors use a nickel based plasmonic spectroscopy system to measure metabolic differences in NK cells that have been exposed to cancer cells as a method of cancer detection.
- Deeptha Ishwar
- , Rupa Haldavnekar
- & Bo Tan
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Article
| Open AccessA brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours
The link between neural development and tumourigenesis in adult glioma remains unclear. Here, the authors monitor the developmental stages of Sox2 + /− stem cells from a mouse model using single-cell RNA sequencing and suggest the acquisition of embryonic-like states in the adult glioma development.
- Akram A. Hamed
- , Daniel J. Kunz
- & Peter B. Dirks
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Article
| Open AccessThe splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors
Leukemic stem cells (LSCs) drive chemoresistance and relapse in acute myeloid leukemia. Here, the authors show that the splicing factor RBM17 supports LSCs through avoiding nonsense-mediated decay of pro-leukaemic factors such as the translation initiation factor EIF4A2.
- Lina Liu
- , Ana Vujovic
- & Yu Lu
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Article
| Open Accessp53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis
The failure of chemotherapy in colorectal cancer is currently unclear. Here, the authors show that upon sub-lethal dose of chemotherapy wild-type p53 colorectal cancers acquire a quiescence-like phenotype and a YAP-dependent fetal-like intestinal stem cell state associated with a higher metastatic activity and poor prognosis in patients.
- Laura Solé
- , Teresa Lobo-Jarne
- & Lluís Espinosa
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Article
| Open AccessCell-lineage controlled epigenetic regulation in glioblastoma stem cells determines functionally distinct subgroups and predicts patient survival
The epigenetic regulation of glioblastoma stem cell (GSC) function remains poorly understood. Here, the authors compare the chromatin accessibility landscape of GSC cultures from mice and patients and suggest that the epigenome of GSCs is cell lineage-regulated and could predict patient survival.
- Xi Lu
- , Naga Prathyusha Maturi
- & Xingqi Chen
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Article
| Open AccessSpatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium
Rapid turnover and regeneration of intestinal epithelium requires distinct intestinal stem cell (ISC) populations. Here the authors show p57 marks quiescent ISCs, and that differentiated cells revert to stem cell state after injury, through dynamic reprogramming characterized by fetal- and metaplastic-like changes.
- Tsunaki Higa
- , Yasutaka Okita
- & Keiichi I. Nakayama
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Article
| Open AccessA non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine
Metabolic reprogramming upon SIRT6 loss induces tumour formation in the intestine but the mechanism is unclear. Here, the authors show that loss of SIRT6 leads to the expansion of epithelial cells with high pyruvate dehydrogenase kinase activity resulting in enhanced stem cell activity and tumour-initiating potential
- Carlos Sebastian
- , Christina Ferrer
- & Raul Mostoslavsky
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Article
| Open AccessCancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis
The contribution of breast cancer stem cells (BCSCs) to metastasis needs further elucidation. Here, the authors show that BCSCs secrete DKK1 to protect metastasizing cancer cells from ferroptosis via upregulation of SLC7A11, and further show that the combination of a ferroptosis inducer with a DKK1 inhibitor reduces metastasis.
- Mingming Wu
- , Xiao Zhang
- & Tao Zhu
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Article
| Open AccessPrimary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells
The understanding of the mechanisms underlying the ability of disseminated tumor cells (DTCs) to form metastasis is incomplete. Here, by using high-resolution intravital imaging of the murine lung to track the fate of breast-derived DTCs, the authors show that macrophages within the primary tumor induce a pro-dissemination and pro-dormancy phenotype in tumor cells, favouring their extravasation in the lung.
- Lucia Borriello
- , Anouchka Coste
- & David Entenberg
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Article
| Open AccessΔNp63 regulates a common landscape of enhancer associated genes in non-small cell lung cancer
The mechanistic role regulated by the oncogene ∆Np63 in lung cancer development is currently unclear. Here, the authors show that ΔNp63 is pro-tumorigenic in lung adenocarcinoma as well as squamous cell carcinoma, and maintains lung cancer progenitor cells via regulation of super-enhancer-associated genes, including BCL9L
- Marco Napoli
- , Sarah J. Wu
- & Elsa R. Flores
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Article
| Open AccessEliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors
Leukemic stem cells (LSCs) in chronic myeloid leukemia are resistant to imatinib and therefore are a cause of relapse. The authors show that IRAK1/4-NF-κB-PD-L1 signaling is critical to mediate imatinib resistance in LSCs and that combining imatinib with blocking this signalling pathway can eliminate LSCs.
- Yosuke Tanaka
- , Reina Takeda
- & Toshio Kitamura
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Article
| Open AccessC/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer
Obesity is linked to cancer risk in post-menopausal breast cancer. At the molecular level this is governed by cellular adaption to palmitic acid through epigenetic activation of a C/EBPB-dependent transcriptional network that drives tumor formation.
- Xiao-Zheng Liu
- , Anastasiia Rulina
- & Nils Halberg
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Article
| Open AccessLive tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination
Intravital imaging reveals macrophage-driven de novo induction of cancer stem cells in vivo, and their dramatic enrichment on dissemination through TMEM doorways. These findings provide a mechanism for the validated ability of TMEM doorway density to be prognostic for distant recurrence of metastatic tumors in breast cancer patients.
- Ved P. Sharma
- , Binwu Tang
- & Maja H. Oktay
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Article
| Open AccessGrowth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma
Poorly differentiated hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis. Here the authors show that GDF1, a member of the TGF-β superfamily, is highly expressed in high-grade poorly differentiated HCC and is associated with tumor plasticity, and that GDF1-induced reexpression of cancer testis antigens could render tumors sensitive to immune checkpoint inhibition.
- Wei Cheng
- , Hao-Long Li
- & Ming Liu
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Article
| Open AccessCompetitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma
SOX2 is required for the maintenance of glioblastoma stem cells (GSCs). Here the authors identify that the RING family E3 ubiquitin ligase TRIM26 promotes SOX2 stability in a non-canonical ligase-independent manner and thus, increases the tumorigenicity of GSCs.
- Tatenda Mahlokozera
- , Bhuvic Patel
- & Albert H. Kim