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Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance
miR-126 is highly expressed in inv(16) Acute myeloid leukemia (AML) but its role is unclear. Here, the authors show that the aberrant expression of miR-126 in inv(16) AML is directly due to the CBFB-MYH11 fusion gene and that it can promote AML development and leukemia stem cell maintenance, highlighting miR-126 as a therapeutic target for inv(16) AML patients
- Lianjun Zhang
- , Le Xuan Truong Nguyen
- & Ya-Huei Kuo
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Article
| Open Access
Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology
Personalized cancer medicine currently lacks custom platforms that mimic the microenvironment of human tissues. Here, the authors show how self-assembled patient-derived models of pancreatic cancer recapitulate key biological features of the original tumours such as matrix composition and stemness.
- David Osuna de la Peña
- , Sara Maria David Trabulo
- & Daniela Loessner
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Long non-coding RNA NR2F1-AS1 induces breast cancer lung metastatic dormancy by regulating NR2F1 and ΔNp63
Disseminated tumor cells often become dormant before awakening for metastatic growth. Here, the authors report that the lncRNA, NR2F1-AS1, is upregulated in dormant mesenchymal-like breast cancer stem-like cells and promotes dissemination but inhibits proliferation, leading to metastatic dormancy.
- Yingjie Liu
- , Peiyuan Zhang
- & Guohong Hu
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ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer
Circulating tumor cell (CTC) clusters are more efficient at mediating metastasis as compared to single cells and are associated with poor prognosis in breast cancer. Here, the authors show that ICAM1 is enriched in CTC clusters and its loss suppresses cell-cell interaction and CTC cluster formation, and propose ICAM1 as a therapeutic target for treating breast cancer metastasis.
- Rokana Taftaf
- , Xia Liu
- & Huiping Liu
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Article
| Open Access
TEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer
Vasculogenic mimicry (VM) contributes to the development of triple-negative breast cancer. In this study, the authors show that TEM8 is expressed in VM-forming breast cancer stem cells and it promotes stemness and VM differentiation capacity through a RhoC/ROCK1/SMAD5 axis
- Jiahui Xu
- , Xiaoli Yang
- & Suling Liu
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| Open Access
Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
Kras is frequently mutated in lung cancer and two isoforms are generated via alternative splicing. Here, the authors show that the two isoforms have divergent roles in cancer stem cells and the main tumour cell population, which are regulated by hypoxia and endoplasmic reticulum stress.
- Wei-Ching Chen
- , Minh D. To
- & Allan Balmain
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Extracellular matrix protein-1 secretory isoform promotes ovarian cancer through increasing alternative mRNA splicing and stemness
Extracellular matrix protein 1 (ECM1) has been associated with cancer but the underlying molecular mechanisms are not clear. Here, the authors show that while ECM1b isoform is a tumour suppressor, the secreted isoform ECM1a promotes tumourigenesis and chemoresistance through increasing stemness and alternative mRNA splicing in ovarian cancer.
- Huijing Yin
- , Jingshu Wang
- & Gong Yang
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| Open Access
Transcriptional super-enhancers control cancer stemness and metastasis genes in squamous cell carcinoma
Little is known on the transcriptional mechanisms that control cancer stem cell (CSC) self-renewal and stemness. Here the authors show superenhancers (SEs) play a role in the transcription of cancer stemness genes as well as prometastatic genes, thereby controlling their tumorigenic potential; disrupting SEs inhibited CSC self-renewal and eliminated CSCs.
- Jiaqiang Dong
- , Jiong Li
- & Cun-Yu Wang
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Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance
How ROS levels are regulated in cancer stem cells and their contribution to cancer resistance is currently not clear. Here, the authors show that prohibitin regulates mitochondrial ROS production stabilizing the peroxidase PRDX3 and this accounts for radiotherapy resistance in glioma stem-like cells.
- Haohao Huang
- , Songyang Zhang
- & Jianghong Man
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Article
| Open Access
Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis
Right-sided colorectal cancer (rCRC) has a different mutational spectrum to the left-sided counterpart. Here the authors develop a mouse model of rCRC that recapitulates human BRAF-mutant rCRC and show that loss of TGFβ-receptor signalling and inflammation induce the development of colonic tumours with a foetal-like phenotype.
- Joshua D. G. Leach
- , Nikola Vlahov
- & Owen J. Sansom
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| Open Access
Quantitative single-cell proteomics as a tool to characterize cellular hierarchies
Single-cell proteomics can provide insights into the molecular basis for cellular heterogeneity. Here, the authors develop a multiplexed single-cell proteomics and computational workflow, and show that their strategy captures the cellular hierarchies in an Acute Myeloid Leukemia culture model.
- Erwin M. Schoof
- , Benjamin Furtwängler
- & Bo T. Porse
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| Open Access
Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation
Human ribonuclease 1 (hRNase 1) regulates innate immunity, hemostasis and RNA clearance. Here, the authors report an alternative function of hRNase 1 as a secretory ligand of Eph receptor EphA4 to enhance breast cancer stemness and promote breast tumour initiation.
- Heng-Huan Lee
- , Ying-Nai Wang
- & Mien-Chie Hung
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Cancer of unknown primary stem-like cells model multi-organ metastasis and unveil liability to MEK inhibition
Cancer of unknown primary (CUP) is a mysterious malignancy featuring metastatic dissemination in the absence of a recognizable primary tumor. By characterizing CUP cancer stem cells we show that self-sustained long-term propagation and sensitivity to MEK inhibition are CUP common features.
- Federica Verginelli
- , Alberto Pisacane
- & Carla Boccaccio
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RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways
RAC1 is a downstream target of the Wnt signaling that promotes intestinal stem cell expansion and tumorigenesis. Here, the authors identify the specific splice variant RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment.
- Victoria Gudiño
- , Sebastian Öther-Gee Pohl
- & Kevin B. Myant
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| Open Access
The white matter is a pro-differentiative niche for glioblastoma
Glioma stem cells (GSCs) retain the ability to partially differentiate, but it is unclear how the brain microenvironment may influence this response. Here the authors show that glioblastoma cells infiltrating into the white matter acquire pre-oligodendrocyte-like fate in a process that mimics myelin repair and results in tumour suppression
- Lucy J. Brooks
- , Melanie P. Clements
- & Simona Parrinello
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FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell
The demethylase FTO was shown to remove on N6-methyladenosine (m6A) and N6, 2’-O-dimethyladenosine (m6Am) modifications on RNAs. Here the authors show that FTO impedes cancer stem cell-like abilities in colorectal cancer cells through its m6Am demethylase activity, not through internal m6A demethylase activity.
- Sébastien Relier
- , Julie Ripoll
- & Alexandre David
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Article
| Open Access
Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics
Leukaemic stem cells drive acute myeloid leukaemia (AML) progression and relapse but they are incompletely characterized. Here, the authors combine single-cell transcriptomics and clonal tracking using nuclear and mitochondrial somatic variants to distinguish healthy, pre-leukaemic and leukaemic stem cells in AML.
- Lars Velten
- , Benjamin A. Story
- & Lars M. Steinmetz
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Patient-derived xenografts and organoids model therapy response in prostate cancer
To date, patients still succumb to cancer, due to tumors not responding to therapy or ultimately acquiring resistance. Here the authors show that by exploiting patient derived organoids and a treatment-naïve patient derived xenograft, patient therapy can be personalized.
- Sofia Karkampouna
- , Federico La Manna
- & Marianna Kruithof-de Julio
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LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells
Regulation of self-renewal is critical during steady state and stress in haematpoietic stem cells (HSCs), and underlies leukaemia pathology. Here, the authors show that LIGHT and its receptor LTβR promote quiescence and self-renewal of HSCs and that LTβR deficiency promotes survival in a mouse leukaemia model.
- S. S. Höpner
- , Ana Raykova
- & A. F. Ochsenbein
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| Open Access
PRMT5 inhibition disrupts splicing and stemness in glioblastoma
The arginine methyltransferase PRMT5 is over-expressed in cancer and has a role in the maintenance of stem cells. Here, the authors show that PRMT5 inhibitors can block the growth of patient derived glioblastoma stem cell cultures in vitro and in vivo, suggesting that PRMT5 inhibition may be a useful therapeutic strategy
- Patty Sachamitr
- , Jolene C. Ho
- & Peter B. Dirks
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Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway
Although activated Notch receptors have been associated with chemoresistance in cancer, the role of specific Notch ligands remain elusive. Here, the authors show that in breast cells the Notch ligand DLL1 is expressed in cells with a cancer stem cell phenotype and promote doxorubicin resistance in part through NF-kB, as well as metastasis.
- Sushil Kumar
- , Ajeya Nandi
- & Rumela Chakrabarti
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Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia
Resistance to tyrosine kinase inhibitors (TKI) is a limitation to their use in treating chronic myelogenous leukemia (CML). Here, the authors show that targeting the ubiquitin peptidase USP47 overcomes TKI resistance and eliminates leukaemia stem/progenitor cells in primary and xenograft CML murine models.
- Hu Lei
- , Han-Zhang Xu
- & Ying-Li Wu
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Article
| Open Access
The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness
Intestinal cancer stem cells (CSC) are associated with colon cancer. Here, the authors show that Wnt/beta-catenin signalling in CSC requires the epigenetic regulator Mll1 to promote stemness and tumourigenesis in murine and human colon cancer models.
- Johanna Grinat
- , Julian Heuberger
- & Walter Birchmeier
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Article
| Open Access
Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells
The tumour microenvironment provides signals to support leukaemic stem cells (LSC) maintenance and chemoresistance. Here, the authors show that disrupting niche-associated signalling by inhibiting receptor-mediated endocytosis with a dynamin GTPase inhibitor overcomes chemoresistance of LSC.
- Cedric S. Tremblay
- , Sung Kai Chiu
- & David J. Curtis
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| Open Access
A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia
Identifying leukaemia stem cells (LSC) and defining how they drive tumourigenesis might aid in the treatment of disease. Here, the authors show that a reporter Musashi 2 can serve as a platform to effectively identify leukemic stem cells and it is used to define Syndecan-1 as a dependency for these aggressive, therapy resistant cells.
- Kyle Spinler
- , Jeevisha Bajaj
- & Tannishtha Reya
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| Open Access
5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation
The relative enrichment of cancer stem cells after treatment results in tumour recurrence. Here, the authors show a mechanism where p53 induces WNT3, which increases the number of colorectal cancer stem cells following treatment of 5-fluorouracil.
- Yong-Hee Cho
- , Eun Ji Ro
- & Kang-Yell Choi
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| Open Access
WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion
Amoeboid cells are associated with melanoma invasive capacity. Here, the authors show that the WNT11-FZD7-DAAM1 pathway regulates tumour-initiating potential, invasion and metastasis lead by amoeboid cells in the invasive front of melanoma tumours.
- Irene Rodriguez-Hernandez
- , Oscar Maiques
- & Victoria Sanz-Moreno
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| Open Access
Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells
Long-term cultures of pancreatic cancer stem cells (PaCSCs) are difficult to obtain. Here, the authors present a 2D culture method, based on the use of galactose, to establish cell cultures from pancreatic ductal adenocarcinoma xenotransplants enriched in PaCSCs.
- Sandra Valle
- , Sonia Alcalá
- & Bruno Sainz Jr
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Article
| Open Access
Jagged1-Notch1-deployed tumor perivascular niche promotes breast cancer stem cell phenotype through Zeb1
The transcription factor Zeb1 is known to promote tumorigenesis and stemness in breast cancer. Here the authors show that tumor endothelial Jagged1 induces activation of Notch1 signaling and increases Zeb1 expression in neighboring breast cancer stem cells, promoting tumor aggressiveness.
- Huimin Jiang
- , Chen Zhou
- & Shuang Yang
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Article
| Open Access
SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells
Cancer stem cells can evade treatment. Here, the authors perform an in vitro screen to identify proteins that are involved in protecting glioma cancer stem cells from therapy and find that SPT6 increases BRCA1 expression and drives error-free DNA repair, thereby ensuring the survival of the cells.
- Elisabeth Anne Adanma Obara
- , Diana Aguilar-Morante
- & Petra Hamerlik
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| Open Access
The lysophospholipase D enzyme Gdpd3 is required to maintain chronic myelogenous leukaemia stem cells
How lipid metabolism can affect cancer recurrence is still unclear. Here, the authors show that the lysophospholipase D Gdpd3 maintains self-renewal capacity of CML stem cells by regulating the quiescence, and AKT/mTORC1 and Foxo3a/β-catenin signalling in an oncogene-independent manner.
- Kazuhito Naka
- , Ryosuke Ochiai
- & Seong-Jin Kim
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Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy
Intratumoural spatial heterogeneity is crucial to enhance therapeutic resistance in glioblastoma. Here, the authors show a paracrine signaling mechanism where glioblastoma-initiating cells located in the tumour edge elevate their malignancy by interaction with core-located tumour cells.
- Soniya Bastola
- , Marat S. Pavlyukov
- & Ichiro Nakano
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| Open Access
Wnt activation as a therapeutic strategy in medulloblastoma
The Wnt molecular subgroup of medulloblastoma is associated with better prognosis than the other molecular subgroups. Here, the authors show that activating Wnt signaling impairs tumor development and improves survival in Group 3 and Group 4 medulloblastoma preclinical models.
- Branavan Manoranjan
- , Chitra Venugopal
- & Sheila K. Singh
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| Open Access
Chlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V
Receptor tyrosine kinase mutations are frequent and associated with poor prognosis in acute myeloid leukemia (AML). Here the authors show that the antipsychotic drug chlorpromazine reduces AML cells viability by perturbing the intracellular localization of FLT3-ITD and KIT-D816V.
- Shinya Rai
- , Hirokazu Tanaka
- & Itaru Matsumura
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| Open Access
OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation
The suppression of the receptor for oncostatin M (OSMR) can prevent glioblastoma cell growth. Here, the authors demonstrate a role for OSMR in modulating glioma stem cell respiration and its impact on resistance to ionizing radiation.
- Ahmad Sharanek
- , Audrey Burban
- & Arezu Jahani-Asl
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Article
| Open Access
An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate
OTX2 promotes tumour growth in Group 3 medulloblastoma. Here, the authors show that OTX2 regulates PAX3 to induce neural de-differentiation and promote tumourigenesis in Group 3 medulloblastoma.
- Jamie Zagozewski
- , Ghazaleh M. Shahriary
- & Tamra E. Werbowetski-Ogilvie
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| Open Access
Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy
Glioblastoma is thought to arise from neural stem cells. Here, to investigate this, the authors use single-cell RNA-sequencing to compare glioblastoma to the fetal human brain, and find a similarity between glial progenitor cells and a subpopulation of glioblastoma cells.
- Charles P. Couturier
- , Shamini Ayyadhury
- & Kevin Petrecca
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Article
| Open Access
Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice
Circadian disruption is implicated in the development of different human cancers. Here the authors show that chronic circadian disruption, through continuous jet lag, only moderately affects primary tumour growth but promotes cancer-cell dissemination and metastasis in a mouse model of spontaneous mammary tumorigenesis.
- Eva Hadadi
- , William Taylor
- & Hervé Acloque
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Article
| Open Access
p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs
Normal stem cells are maintained by asymmetric cell division, but this process is dysregulated in tumour initiating stem-like cells (TICs). Here, the authors show that TBC1D15 impairs the asymmetric division machinery and activates NOTCH pathway for TIC self-renewal and expansion to promote liver tumorigenesis.
- Hye Yeon Choi
- , Hifzur R. Siddique
- & Keigo Machida
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Article
| Open Access
ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages
How glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) interact to promote progression of glioblastoma multiforme (GBM) is currently unclear. Here, the authors demonstrate a role for the ARS2/MAGL signalling in regulating self-renewal and tumorigenicity of GSCs and M2-like TAM polarization.
- Jinlong Yin
- , Sung Soo Kim
- & Jong Bae Park
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Article
| Open Access
ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
The ubiquitin-like modifier ISG15 exerts post-translational protein regulation through ISGylation. Here, the authors show that ISGylation is necessary for pancreatic cancer stem cell self-renewal and tumourigenesis by supporting the recycling of non-functional mitochondria.
- Sonia Alcalá
- , Patricia Sancho
- & Bruno Sainz Jr
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Article
| Open Access
SH3RF3 promotes breast cancer stem-like properties via JNK activation and PTX3 upregulation
Cancer stem-like cells are the culprits of tumour recurrence and metastasis, but their regulatory mechanisms are not fully understood. Here, the authors show that the scaffold protein SH3RF3 enhances the stem-like properties of breast cancer by facilitating activation of the JNK-JUN pathway and PTX3 expression.
- Peiyuan Zhang
- , Yingjie Liu
- & Guohong Hu
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Article
| Open Access
Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance
The cell adhesion molecule E-selectin regulates haematopoietic stem cell self-renewal in the bone marrow vascular niche. Here, the authors show E-selectin adhesion directly induces survival signaling in acute myeloid leukaemia and therapeutic inhibition improves chemotherapy outcomes in mice.
- Valerie Barbier
- , Johanna Erbani
- & Ingrid G. Winkler
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Article
| Open Access
HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells
The identification of mRNA targets for RNA binding proteins (RBP) in stem cells is difficult due to the limited number of available cells. Here, as a proof-of-principle, the authors adapt the HyperTRIBE method to find that an RBP, MSI2, has increased RNA binding in leukemic compared with normal stem cells for selective regulation of oncogenic genes.
- Diu T. T. Nguyen
- , Yuheng Lu
- & Michael G. Kharas
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Article
| Open Access
LGR5 marks targetable tumor-initiating cells in mouse liver cancer
Cancer stem cells (CSCs) are thought to be the main drivers for disease progression and treatment resistance in liver cancer. This study identifies the LGR5+ compartment as an important CSC population, representing a viable therapeutic target for combating liver cancer.
- Wanlu Cao
- , Meng Li
- & Qiuwei Pan
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Article
| Open Access
Quantum scale organic semiconductors for SERS detection of DNA methylation and gene expression
The low detection sensitivity of organic semiconductors has limited their use in biomedical surface-enhanced Raman scattering applications. Here, the authors use quantum scale organic semiconductors and show detection of genomic DNA methylation as well as gene expression.
- Swarna Ganesh
- , Krishnan Venkatakrishnan
- & Bo Tan
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Article
| Open Access
Tracing tumorigenesis in a solid tumor model at single-cell resolution
Understanding tumour development at a granular level is a challenge in solid tumours. Here, the authors provide a cell atlas across tumour development in a genetic model of salivary gland squamous cell carcinoma using single-cell transcriptome and epitope profiling.
- Samantha D. Praktiknjo
- , Benedikt Obermayer
- & Nikolaus Rajewsky
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Article
| Open Access
FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML
FOXM1 is a known transcription factor which promotes cell proliferation in cancer cells. Here, the authors show that FOXM1 is required for the maintenance of quiescence and self-renewal of leukemia stem cells in MLL-AF9-rearranged acute myeloid leukemia patient and mouse models.
- Yue Sheng
- , Chunjie Yu
- & Zhijian Qian
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Article
| Open Access
Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients
Cancer stem cells are thought to be largely resistant to treatment and can be responsible for tumour recurrence. Here, using renal cancer organoids, self-renewing sphere cultures and PDX from patients, the authors show that the proliferation of stem cells within organoids, PDX and spheres can be blocked by the concomitant inhibition of the NOTCH and WNT pathways.
- Annika Fendler
- , Daniel Bauer
- & Walter Birchmeier
N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism