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| Open AccessCompartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage
The mechanisms regulating the balance between proliferation and differentiation in medulloblastomas with extensive nodularity (MBEN) remain poorly understood. Here, single cell multi-omics and spatial analysis characterises the spatial tissue organisation of MBEN in the context of the developmental trajectory.
- David R. Ghasemi
- , Konstantin Okonechnikov
- & Kristian W. Pajtler
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Article
| Open AccessMulti-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions
The molecular characteristics and therapeutic vulnerabilities of TFCP2-rearranged rhabdomyosarcomas (RMS) require further exploration. Here, the authors use multi-omics analyses and functional and mechanistic investigations to characterize TFCP2-rearranged RMS – including cases with FUS/EWSR1-TFCP2 fusions – across two precision oncology programs.
- Julia Schöpf
- , Sebastian Uhrig
- & Claudia Scholl
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Article
| Open AccessMouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures
Paediatric high-grade gliomas with MYCN amplification (HGG-MYCN) are rare and highly aggressive. Here, the authors generate a mouse model for HGG-MYCN that can recapitulate the histological and molecular profiles of the human tumours, and perform high-throughput drug screening to identify potential treatment options.
- Melanie Schoof
- , Shweta Godbole
- & Ulrich Schüller
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Article
| Open AccessSpatial transcriptomics analysis of esophageal squamous precancerous lesions and their progression to esophageal cancer
Understanding the molecular changes in the transition from esophageal squamous precancerous lesions (ESPL) to esophageal squamous cell carcinoma (ESCC) remains essential. Here, the authors analyze ESPL samples using spatial transcriptomics and reveal expression changes in TAGLN2 and CRNN during progression to ESCC.
- Xuejiao Liu
- , Simin Zhao
- & Zigang Dong
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Article
| Open Accessp53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition
Ageing normal oesophagus epithelium contains p53 mutant clones. Here the authors use transgenic mice to show how these clones form and contribute to cancer development.
- Kasumi Murai
- , Stefan Dentro
- & Philip H. Jones
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Article
| Open AccessOXTRHigh stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling
Worst pattern of invasion (WPOI) is a parameter used to quantify tumor invasiveness of oral squamous cell carcinoma (OSCC). Here the authors show that a fibroblast subset characterized by the expression of the oxytocin receptor is enriched in highly invasive WPOI 4-5 OSCC tumors and can be targeted to reduce the desmoplastic stroma and tumor metastasis.
- Liang Ding
- , Yong Fu
- & Yanhong Ni
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Article
| Open AccessEstrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor
The role of progesterone receptor (PR) and its interplay with estrogen receptor (ER) in breast cancer is controversial. Here, the authors demonstrate that PR can have an ER-independent role in breast cancer growth and metastasis and that its effects are dependent on MYC and androgen receptor signatures.
- Valentina Scabia
- , Ayyakkannu Ayyanan
- & Cathrin Brisken
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Article
| Open AccessSingle-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma
Cutaneous T cell lymphomas (CTCL) are still poorly characterised at the molecular and single-cell level. Here, the authors analyse CTCL patient samples using single-cell RNA-seq, TCR and whole-exome sequencing, revealing the molecular profiles of malignant T cells and their association with the microenvironment and clinical outcomes.
- Xiangjun Liu
- , Shanzhao Jin
- & Yang Wang
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Article
| Open AccessDeciphering spatial genomic heterogeneity at a single cell resolution in multiple myeloma
Osteolytic lesions (OL) are frequent in multiple myeloma (MM), but are poorly understood. Here, the authors characterise OLs in MM patient samples using single-cell RNA-seq, revealing genes that are specifically regulated in OL compared to random bone marrow aspirates and that reflect the response to induction therapy.
- Maximilian Merz
- , Almuth Maria Anni Merz
- & Jens Hillengass
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Article
| Open AccessA human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program
It is unknown why infant acute lymphoblastic leukemia (ALL) produced by MLL rearrangements leads to worse outcomes than childhood ALL. Here the authors develop a CRISPR-Cas9-induced human xenograft model of MLL-AF4 infant-ALL that faithfully replicates the disease and reveals that fetal-specific genes are potential infant-ALL drivers.
- Siobhan Rice
- , Thomas Jackson
- & Anindita Roy
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Article
| Open AccessQuantitative proteomic landscape of metaplastic breast carcinoma pathological subtypes and their relationship to triple-negative tumors
Metaplastic breast carcinoma (MBC) is among the most aggressive subtypes of triple-negative breast cancer (TNBC) but the underlying proteome profiles are unknown. Here, the authors characterize the protein signatures of human MBC tissue samples and their relationship to TNBC and normal breast tissue.
- Sabra I. Djomehri
- , Maria E. Gonzalez
- & Celina G. Kleer
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Article
| Open AccessOrganoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages
Organoid technology has enabled the generation of several breast cancer organoids. Here, the authors combine propagation of normal human mammary tissues with mass cytometry to evaluate the ability of organoid culture technologies to preserve stem cells and differentiated cell types.
- Jennifer M. Rosenbluth
- , Ron C. J. Schackmann
- & Joan S. Brugge
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Article
| Open AccessTracing 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 AccessEVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription
Chr3q26 rearrangements cause overexpression of EVI1 and associate with myeloid neoplasms, but the mechanism behind this association is unclear. Here, using a novel mouse model they show that EVI1 causes premalignant myeloid expansion with suppression of other lineages through upregulation of Spi1/PU.1.
- Edward Ayoub
- , Michael P. Wilson
- & Archibald S. Perkins
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Article
| Open AccessCombined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi
Deep penetrating nevi (DPN) are unusual melanocytic neoplasms with unknown genetic drivers. Here the authors show that majority of DPN harbor activating mutations in the β-catenin and the MAP-kinase pathways; this characteristic can help in the classification and grading of these distinctive neoplasms.
- Iwei Yeh
- , Ursula E. Lang
- & Arnaud de la Fouchardière
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Article
| Open AccessThe landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis
Genetically engineered mouse models of cancer are useful in identifying oncogenes and tumour suppressors. Here, the authors use gene expression profiles to generate a catalogue of copy number aberrations in 45 mouse models, and compare mouse and human tumours to identify additional drivers of tumorigenesis.
- Uri Ben-David
- , Gavin Ha
- & Todd R. Golub
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Article
| Open AccessIL-13 from intraepithelial lymphocytes regulates tissue homeostasis and protects against carcinogenesis in the skin
Epidermal intraepithelial lymphocytes (IEL) produce IL-13, but the physiological role of this cytokine production is not clear. Here the authors show that IEL-production of IL-13 is a vital lymphoid stress surveillance mechanism driving crosstalk with epithelial cells to maintain tissue homeostasis and inhibit chemical carcinogenesis in mice.
- Tim Dalessandri
- , Greg Crawford
- & Jessica Strid
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Article
| Open AccessTumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression
miRNAs can function either as proto-oncogenes or tumour suppressors in several cancers; however their function in tumour initiating cells is unclear. Here, Zhang et al. show that tumour initiating cell-specific miR-1246 and miR-1290 promote lung cancer initiation and metastasis and could serve as prognostic markers.
- Wen Cai Zhang
- , Tan Min Chin
- & Bing Lim
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Article
| Open AccessKRT14 marks a subpopulation of bladder basal cells with pivotal role in regeneration and tumorigenesis
It is unclear whether there is a progenitor/stem cell in the basal layer of the urothelium in the bladder. Here, the authors identify Keratin14 positive cells that can regenerate the bladder in both a natural and injury-induced manner, and following neoplastic transformation, can give rise to tumours.
- George Papafotiou
- , Varvara Paraskevopoulou
- & Apostolos Klinakis
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Article
| Open AccessHomeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics
The homeobox NKX2 family of transcriptional factors has been shown to regulate fundamental developmental processes. Here, the authors show that NKX2-3 is a bona fideoncogenic driver in marginal-zone B-cell lymphoma and that it promotes lymphomagenesis by shaping lymphocyte dynamics and promoting BCR signalling.
- Eloy F. Robles
- , Maria Mena-Varas
- & Jose A. Martinez-Climent
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Article
| Open AccessA splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation
The Hippo/Yap signalling pathway is found deregulated in several cancers. Here, the authors uncover an additional mechanism of YAP regulation that occurs via alternately spliced isoform of TEAD4, which acts as a dominant negative regulator of YAP-TEAD signalling.
- Yangfan Qi
- , Jing Yu
- & Zefeng Wang
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Article
| Open AccessGPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis
GPRC5A is a retinoic acid inducible gene that is preferentially expressed in lung tissue. Here the authors report that GPRC5A suppresses the translation of EGFR by interfering with the eIF4F complex assembly, thereby limiting lung tumorigenesis, particularly radiation-induced lung tumorigenesis.
- Jian Wang
- , Alton B. Farris
- & Ya Wang
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Article
| Open AccessCXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment
Adipose stromal cells (ASC) have been shown to migrate to tumours and promote tumour growth. Using animal models and human tissue samples, the authors show here that ASC recruitment to prostate cancers is mediated by the chemokine CXCL1, which is secreted from tumour cells, and acts on CXCR1 on ASCs.
- Tao Zhang
- , Chieh Tseng
- & Mikhail G. Kolonin
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Article
| Open AccessMacrophage ABHD5 promotes colorectal cancer growth by suppressing spermidine production by SRM
ABHD5 is a co-activator of lipolysis. Here the authors show that in tumour-associated macrophages ABHD5 inhibits ROS-dependent induction of C/EBPɛ, which transcriptionally activates spermidine synthase, and that blocking ABHD5 delays colorectal cancer growth in mice by inhibiting spermidine production.
- Hongming Miao
- , Juanjuan Ou
- & Houjie Liang
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Article
| Open AccessERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation
It is unclear how the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways interact with other signals in intestinal epithelial cells. Here, the authors show that upon loss of Erk1/2, or pharmacological inhibition of MEK1/2, the ERK5 pathway is upregulated to maintain epithelial cell proliferation.
- Petrus R. de Jong
- , Koji Taniguchi
- & Eyal Raz
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Article
| Open AccessTumour resistance in induced pluripotent stem cells derived from naked mole-rats
The naked mole-rat exhibits an exceptional resistance to cancer. Here, the authors show that induced pluripotent stem cells derived from the naked mole-rat lack teratoma-forming tumorigenicity due to a naked mole-rat-specific ARF-dependent tumour-suppression mechanism.
- Shingo Miyawaki
- , Yoshimi Kawamura
- & Kyoko Miura
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Article
| Open AccessDNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells
De novoDNA methylation is carried out by DNA methyltransferase DNMT3A/B, although DNMT3B isoforms without active catalytic domains are widely expressed. Here, the authors show that DNMT3B isoforms stimulate gene body methylation and re-methylation independently of the isoforms' catalytic activity.
- Christopher E. Duymich
- , Jessica Charlet
- & Gangning Liang
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Article
| Open AccessZyxin-Siah2–Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways
Hippo and TGF-β are crucial signalling pathways involved in the development of various types of tumours. Here, the authors demonstrate that TGF-β can directly regulate Hippo pathway through the stabilization of the scaffold protein Zyxin, which forms a ternary complex with Siah2 and Lats2 promoting Lats2 degradation and YAP activation.
- Biao Ma
- , Hongcheng Cheng
- & Yushan Zhu
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Article
| Open AccessCoagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis
It is unclear whether cancer-related hypercoagulation and neutrophilia contribute to tumorigenesis. In this study, the authors find that activation of the complement cascade causes hypercoagulation that leads to polarization of neutrophils in a mouse model of intestinal cancer, and show that blocking complement activation can reduce tumour formation.
- Silvia Guglietta
- , Andrea Chiavelli
- & Maria Rescigno
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Article
| Open AccessPolycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network
Polycomb-mediated gene regulation has been implicated in gliomas. Here the authors integrate transcriptomic and epigenomic analyses to define Polycomb-dependent networks that promote gliomagenesis, and find that the Polycomb-dependent silencing of the transcription factor Zfp423hinders survival.
- Elena Signaroldi
- , Pasquale Laise
- & Giuseppe Testa
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Article
| Open AccessA monoclonal antibody against KCNK9 K+ channel extracellular domain inhibits tumour growth and metastasis
The potassium channel KCNK9 mediates important biological processes and is often overexpressed in breast and lung cancers. In this study, the authors developed a specific monoclonal antibody against the extracellular domain of KCNK9 and show that it inhibits cancer growth and metastasis in vivothrough both cell autonomous and immune-dependent cellular cytotoxicity.
- Han Sun
- , Liqun Luo
- & Min Li
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Article
| Open AccessC1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation
C1q is known to initiate the activation of the complement classical pathway. Here, the authors show the C1q is expressed in the tumour microenvironment and can promote cancer cell migration and adhesion in a complement activation-independent manner.
- Roberta Bulla
- , Claudio Tripodo
- & Francesco Tedesco
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Article
| Open AccessDefective DNA single-strand break repair is responsible for senescence and neoplastic escape of epithelial cells
It is recognized that cellular senescence is triggered by DNA damage as a protective mechanism against tumorigenesis. Here the authors show that DNA single-strand breaks of oxidative origin can induce a transient senescent state followed by the emergence of clonal transformed cells.
- Joe Nassour
- , Sébastien Martien
- & Corinne Abbadie
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Article
| Open AccessDNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer
Altered epigenetics is a feature of cancer but whether these changes occur early in tumour development is unclear. Here, the authors analyse methylation events in breast cancer and adjacent normal pairs, and show that methylation changes in the normal tissue are also found in the tumour, suggesting that some of these events occur early in cancer.
- Andrew E Teschendorff
- , Yang Gao
- & Martin Widschwendter
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Article
| Open AccessThe occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation
SMARCB1 inactivation is prevalent in human atypical teratoid/rhabdoid tumours but a mouse model that accurately phenocopies the human disease is lacking. Here, the authors show that inactivation of SMARCB1between E6 and E10 in mice results in tumours that better recapitulate the human phenotype, compared to previously reported models.
- Zhi-Yan Han
- , Wilfrid Richer
- & Franck Bourdeaut
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Article
| Open AccessPeriprostatic adipocytes act as a driving force for prostate cancer progression in obesity
Obesity is associated with an elevated risk of prostate cancer. Here, the authors show that periprostatic adipose tissue promotes the migration and local invasion of prostate cancer cells by secreting the chemokine, CCL7, and that this process is enhanced in the context of obesity.
- Victor Laurent
- , Adrien Guérard
- & Catherine Muller
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Article
| Open AccessBPTF is required for c-MYC transcriptional activity and in vivo tumorigenesis
c-MYC genomic distribution is dictated by the epigenetic context but the mechanisms are unknown. Here, the authors show that c-MYC requires the chromatin reader BPTF to activate its transcriptional program and promote tumour development in vivo, suggesting that BPTF is a potential target for cancer therapy.
- Laia Richart
- , Enrique Carrillo-de Santa Pau
- & Francisco X. Real
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Article
| Open AccessAccumulation of differentiating intestinal stem cell progenies drives tumorigenesis
Intestinal homeostasis is ensured by stem cell self-renewal and differentiation while alterations of these processes can lead to cancer. In this study, using Drosophilagenetics the authors demonstrate that the loss of the transcription factor Sox21a blocks the differentiation of the intestinal stem cell progeny, which accumulate and form aggressive tumours.
- Zongzhao Zhai
- , Shu Kondo
- & Bruno Lemaitre
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Article
| Open AccessRecruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression
E2F transcription factors are primarily known for the regulation of the cell cycle and are often dysregulated in cancer. Here, the authors show that during cancer progression E2F1 recruits a Pontin/Reptin complex to E2F target genes to open chromatin and increase E2F transcriptional response.
- Amy Tarangelo
- , Nathanael Lo
- & Patrick Viatour
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Article
| Open AccessInhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis
Aberrant Ras signalling resulting in downstream Mek/Erk pathway activation is found in many cancers. Here, the authors show that the phosphatase SHP2 dephosphorylates Ras resulting in increased Ras activity, and that increased SHP2 activity is found in glioblastomas.
- Severa Bunda
- , Kelly Burrell
- & Michael Ohh
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Article |
Saturated fatty acids regulate retinoic acid signalling and suppress tumorigenesis by targeting fatty acid-binding protein 5
Long chain fatty acids can influence the growth of cancer cells but the mechanisms involved are unclear. Here, the authors show that both saturated and unsaturated long chain fatty acids can influence retinoic acid signalling and suppress tumour growth in mice.
- Liraz Levi
- , Zeneng Wang
- & Noa Noy
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Article
| Open AccessAF4 uses the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP-dependent transcription
Protein fusions between MLL and AEP (AF4 family/ENL family/P-TEFb) constitutively activate their target genes to immortalize hematopoietic progenitors. Here, Okuda et al. show that MLL-AEP binds SL1, a component of the pre-initiation complex of RNA polymerase (RNAP) I, to initiate RNAP II dependent transcription.
- Hiroshi Okuda
- , Akinori Kanai
- & Akihiko Yokoyama
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Article
| Open AccessRecurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney
The genetic basis of clear cell sarcomas of the kidney is not well understood. In this study, Roy et al. perform whole-exome and RNA sequencing of these tumours and identify recurrent internal tandem duplications in BCOR, a key constituent of a variant polycomb repressive complex.
- Angshumoy Roy
- , Vijetha Kumar
- & D. Williams Parsons
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Article
| Open AccessmiR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth
The synergism between c-MYC and miR-17-19b plays an important role in lymphoma initiation. In this study, the authors identify a panel of targets co-regulated by miR-17-19b and in MYC-driven lymphoma and unravel the molecular mechanism through which miR-17-19b inhibits MYCtranslation.
- Marija Mihailovich
- , Michael Bremang
- & Tiziana Bonaldi
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Article
| Open AccessBAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages
BAG3 is found in the serum of pancreatic cancer patients and can be used as a marker of disease, but its role in cancer is unclear. Here, the authors show that BAG3 secreted from tumour cells binds to and activates macrophages, which in turn promotes cell growth, and an antibody blocking BAG3 binding reduces tumour formation in mice.
- Alessandra Rosati
- , Anna Basile
- & Maria Caterina Turco
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Article
| Open AccessGut mucosal microbiome across stages of colorectal carcinogenesis
Changes in gut microbial communities contribute to the development of colorectal cancer. Here, the authors analyse the gut mucosal microbiome of patients and healthy subjects and identify distinct microbial consortia associated with different stages of colorectal cancer tumorigenesis.
- Geicho Nakatsu
- , Xiangchun Li
- & Joseph J. Y. Sung
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Article
| Open AccessPOH1 deubiquitylates and stabilizes E2F1 to promote tumour formation
The transcription factor E2F1 controls the expression of multiple genes and is frequently overactivated in cancer. Here, the authors show that E2F1 is deubiquitinated by POH1 and that this enhances the role of E2F1 in cell survival, and contributes to the pathogenesis of liver cancer.
- Boshi Wang
- , Aihui Ma
- & Yongzhong Liu
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Article
| Open AccessModel of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells
With no cell lines available, investigating the aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs) has proved problematic. Here, Oikawa et al. establish a model of hFL-HCCs as a transplantable tumour line maintained in immune-compromised mice, which proves rich in cancer stem cells.
- Tsunekazu Oikawa
- , Eliane Wauthier
- & Lola M. Reid
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Article
| Open AccessLoss of KLF14 triggers centrosome amplification and tumorigenesis
Centrosome amplification is common in cancer, but the mechanism is not clear. Here the authors uncover a role for Kruppel-like factor 14 (KLF14) as a transcriptional repressor of polo-like kinase 4 (PLK4); KLF14 depletion correlates with increased PLK4 in human samples and leads to centrosome amplification and tumorigenesis in mice.
- Guangjian Fan
- , Lianhui Sun
- & Chuangui Wang