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| Open AccessAutophagy inhibition prevents lymphatic malformation progression to lymphangiosarcoma by decreasing osteopontin and Stat3 signaling
Lymphatic malformation (LM) is a rare, non-malignant vascular abnormality that can progress to lymphangiosarcoma (LAS). The authors use genetic mouse models to show that autophagy inhibition blocks the progression of LM to LAS by decreasing osteopontin expression and Jak/Stat signalling.
- Fuchun Yang
- , Shiva Kalantari
- & Jun-Lin Guan
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Article
| Open AccessPolycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors
Delineating the specific role of Polycomb Repressive Complex 2 (PRC2) in various cancer systems is desirable as inhibitors for EZH2 inhibitors are approved for some cancers. Here the authors show haplo- and full-insufficiency of EZH2 drive divergent phenotypes in lung cancer. 3D tumoroids recapitulate transcriptional profiles, including FOXP2 derepression, and drug responses of in vivo tumors.
- Fan Chen
- , Aria L. Byrd
- & Christine Fillmore Brainson
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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 AccessIntegrative analysis of multiple genomic data from intrahepatic cholangiocarcinoma organoids enables tumor subtyping
There is still need for representative models of intrahepatic cholangiocarcinoma (ICC) subtypes. Here, the authors develop organoids for two recently suggested ICC subtypes and identify distinct transcriptional profiles and potential therapeutic targets.
- Hee Seung Lee
- , Dai Hoon Han
- & Jun Yong Park
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Article
| Open AccessCD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer
The origin of cancer-associated fibroblasts (CAFs) in cancer remains to be identified. Here, single-cell transcriptomics, in vivo and in vitro studies suggest that CD26+ and CD26- normal fibroblasts transform into distinct CAF subpopulations in mouse models of breast cancer.
- Julia M. Houthuijzen
- , Roebi de Bruijn
- & Jos Jonkers
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Article
| Open AccessDysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter’s transformation
Richter’s Transformation is a treatment-resistant and fatal progression from Chronic Lymphocytic Leukemia (CLL) to an aggressive lymphoma. Here, the authors show that PRMT5 is upregulated months prior to and after transformation, PRMT5 overexpression in a CLL mouse model leads to increased risk of transformation, and that targeted PRMT5 inhibition prolongs survival and delays disease development.
- Zachary A. Hing
- , Janek S. Walker
- & Rosa Lapalombella
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Article
| Open AccessEpithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features
It remains critical to identify colorectal cancers (CRC) that will disseminate as early as possible. Here, the authors identify CRC tumours that are aggressive and prone to early dissemination, characterised by epithelial TGFβ and growth-factor signalling - which could be targeted with MEK/EGFR inhibitors.
- Dustin J. Flanagan
- , Raheleh Amirkhah
- & Owen J. Sansom
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Article
| Open AccessBreast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis
LATS1 is reported to regulate the transition of luminal-basal-like cell plasticity in breast cancer. Here the authors report that LATS1 limits the progression of luminal breast cancer by associating with NCOR1 nuclear corepressor to repress ERα-downregulated genes in luminal cells.
- Yael Aylon
- , Noa Furth
- & Moshe Oren
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Article
| Open AccessEvaluating cancer etiology and risk with a mathematical model of tumor evolution
Modelling how endogenous mutations accumulate in tissues is valuable to understand how cancers develop and evolve. Here, the authors establish a mathematical model that can predict the number of endogenous somatic mutations in the lifetime of tissues and approximate the time to cancer development.
- Sophie Pénisson
- , Amaury Lambert
- & Cristian Tomasetti
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Article
| Open AccessPolymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models
Nanotherapy has potential utility in cancer, particularly in targeted delivery of therapeutics. Here the authors demonstrate delivery of tranilast loaded micelles to improve the reprogramming of cancer associated fibroblasts and monitor tumour stiffness to predict responses.
- Myrofora Panagi
- , Fotios Mpekris
- & Triantafyllos Stylianopoulos
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Article
| Open AccessStromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis
Prostate stromal cells can contribute to prostate tumorigenesis. Here the authors show that the loss of androgen receptor signalling in Gli1-lineage stromal cells diminishes prostate epithelial oncogenic transformation and tumor growth in mouse models and this is due to insulin-like growth factor binding protein 3-mediated inhibiting IGF1 and Wnt/β-catenin signalling activation.
- Alex Hiroto
- , Won Kyung Kim
- & Zijie Sun
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Article
| Open AccessClonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer
Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma. Here we show that identification of clonal somatic copy number alterations in frequently amplified cancer genes could inform therapeutics for precision medicine.
- Filipe Correia Martins
- , Dominique-Laurent Couturier
- & James D. Brenton
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Article
| Open AccessCommon anti-cancer therapies induce somatic mutations in stem cells of healthy tissue
Specific anti-cancer therapies are highly mutagenic to cancer cells but the mutational impact on healthy tissues remains elusive. Here, the authors use organoids and whole-genome sequencing to characterise somatic mutations in healthy colon and liver adult stem cells after chemo- or radiotherapy.
- Ewart Kuijk
- , Onno Kranenburg
- & Arne Van Hoeck
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Article
| Open AccessGene expression based inference of cancer drug sensitivity
Predicting treatment response in cancer remains a highly complex task. Here, the authors develop Precily, a deep neural network framework to predict treatment response in cancer by considering gene expression, pathway activity estimates and drug features, and test this method in multiple datasets and preclinical models.
- Smriti Chawla
- , Anja Rockstroh
- & Debarka Sengupta
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Article
| Open AccessHigh p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.
- Marta Palafox
- , Laia Monserrat
- & Violeta Serra
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Article
| Open AccessSpatiotemporal dynamics of self-organized branching in pancreas-derived organoids
Pancreatic ductal adenocarcinomas (PDAC) exhibit complex morphologies challenging to capture in organoid models. Here, the authors develop PDAC organoids that can recreate branched structures and, with the use of a minimal mathematical model, shed light to pathways and processes directing the dynamics of self-organization and branching morphogenesis.
- S. Randriamanantsoa
- , A. Papargyriou
- & A. R. Bausch
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Article
| Open AccessEpithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence
The study of tumour dormancy is limited by suitable in vivo models. Here the authors show that mammary intraductal breast cancer (BC) xenografts model estrogen receptor α-positive (ER+) BC dormancy and rapid metastatic progression characteristic of triple-negative (TN) BC. The dormant disseminated ER+ BC cells display characteristics of epithelial-mesenchymal plasticity and forced expression of E-cadherin allows them to overcome dormancy.
- Patrick Aouad
- , Yueyun Zhang
- & Cathrin Brisken
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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 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 AccessAberrant androgen action in prostatic progenitor cells induces oncogenesis and tumor development through IGF1 and Wnt axes
Activation of the androgen receptor (AR) through androgen binding is essential for prostate tumorigenesis. Here the authors show that AR activation in a subpopulation of prostatic progenitor cells can initiate prostatic intraepithelial neoplasia formation and promotes prostate cancer development through activation of IGF1 and Wnt/β-catenin signalling pathways.
- Won Kyung Kim
- , Adam W. Olson
- & Zijie Sun
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Article
| Open AccessLymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC
Response rates to immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) remain low. Here the authors show that ablative treatment of tumor-draining regional lymphatics, a standard of care approach in patients, impairs the tumor response to ICI in preclinical HNSCC models.
- Robert Saddawi-Konefka
- , Aoife O’Farrell
- & J. Silvio Gutkind
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Article
| Open AccessOncogenic BRAF induces whole-genome doubling through suppression of cytokinesis
Whole-genome doubling (WGD) commonly occurs in many solid tumors. Here the authors use a zebrafish model of melanoma and in vitro models to show that BRAFV600E induces WGD via inhibition of RhoA and cytokinesis failure.
- Revati Darp
- , Marc A. Vittoria
- & Craig J. Ceol
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Article
| Open AccessResults of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer
FGFR-1 upregulation has been associated with endocrine therapy resistance in breast cancer patients. Here the authors report the results of a phase IIa study to assess the safety and efficacy of AZD454, an inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases, in combination with anastrozole or letrozole, in estrogen receptor positive breast cancer patients.
- R. C. Coombes
- , P. D. Badman
- & M. J. Seckl
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Article
| Open AccessEnhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation
The factors that determine the distinct profiles of NRAS mutants across different tumor types remain unclear. Here, the authors use an allelic series of conditional mouse models to investigate the molecular mechanisms underlying the enrichment of specific NRAS mutants in human melanoma
- Brandon M. Murphy
- , Elizabeth M. Terrell
- & Christin E. Burd
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Article
| Open AccessThe drug-induced phenotypic landscape of colorectal cancer organoids
The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.
- Johannes Betge
- , Niklas Rindtorff
- & Michael Boutros
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Article
| Open AccessAn integral genomic signature approach for tailored cancer therapy using genome-wide sequencing data
Predicting drug responses in cancer patients requires robust computational frameworks. Here, the authors develop an integral genomic signature —iGenSig— approach to predict drug responses using multi-omics data from tumour samples, and validate this approach using genomic datasets from multiple clinical studies.
- Xiao-Song Wang
- , Sanghoon Lee
- & Yue Wang
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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 AccessRNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer
The influence of mRNA splicing on colon cancer development and progression is unclear. In this study, the authors demonstrate that the SRSF1 splicing factor is essential to sustain the stem cell phenotype of WNT-activated colorectal cancers.
- Adam E. Hall
- , Sebastian Öther-Gee Pohl
- & Kevin B. Myant
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Article
| Open AccessNeuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1
Neuronal activity is emerging as a driver of nervous system tumors. Here, the authors show in mouse models of Neurofibromatosis-1 (NF1) that Nf1 mutations differentially drive both central and peripheral nervous system tumor growth in mice through reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function.
- Corina Anastasaki
- , Juan Mo
- & David H. Gutmann
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Article
| Open AccessMYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets
The role of MYC in transcriptional reprogramming in prostate cancer remains poorly characterized. Here, MYC overexpression antagonizes the canonical AR transcriptional program leading to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.
- Xintao Qiu
- , Nadia Boufaied
- & David P. Labbé
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Article
| Open AccessRapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ
Pancreatic intraepithelial neoplasia (PanIN) can develop into pancreatic ductal adenocarcinoma (PDAC), however, the factors which determine how this occurs are unknown. Here, the authors illustrate the role of PPARδ in the upregulation of CCL2, resulting in an immunosuppressive microenvironment, and driving the progression of PanIN to PDAC.
- Yi Liu
- , Yasunori Deguchi
- & Imad Shureiqi
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Article
| Open AccessIRF4 drives clonal evolution and lineage choice in a zebrafish model of T-cell lymphoma
IRF4 is a regulator of immune function, and is overexpressed in lymphoid neoplasms. Here, the authors utilise single cell RNA-seq to show the abundance of double-negative T cells in IRF4 driven zebrafish tumour models, and identify sensitivity of these tumours to BRD inhibition.
- Stella Amanda
- , Tze King Tan
- & Takaomi Sanda
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Article
| Open AccessPathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation
Female carriers of BRCA1 mutations possess high breast cancer risk, which may reflect deficient growth control of mammary progenitor cells. Here, the authors study progenitor-enriched fractions from these carriers and describe a loss of PLK1-mediated mitotic spindle positioning and an inability of the progeny to acquire features of mature luminal cells.
- Zhengcheng He
- , Ryan Ghorayeb
- & Christopher A. Maxwell
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Article
| Open AccessSingle-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer
Cell senescence remains a barrier to tumor elimination in many cancers. Here, the authors use single cell RNA-seq to identify a role for Mcl-1 in senescent cell survival, and show that Mcl-1 inhibition may be an effective therapeutic strategy.
- Martina Troiani
- , Manuel Colucci
- & Andrea Alimonti
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Article
| Open AccessUSP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer
The biological roles of deubiquitinating enzymes (DUBs) in pancreatic ductal adenocarcinoma (PDAC) are not fully explored. Here the authors perform activity based proteomics with a loss of function genetic screen and identify that USP25 promotes PDAC growth and survival through HIF-1 protein stability and transcriptional activity.
- Jessica K. Nelson
- , May Zaw Thin
- & Axel Behrens
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| Open AccessHeterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models
Molecular subtypes of small cell lung cancer characterized by neuroendocrine differentiation have been described in cell lines and primary tumors. The clinical implications of neuroendocrine subtypes in metastatic and relapsed tumors, and the extent to which the subtype distribution is recapitulated in patient-derived models remains unclear. Here, the authors integrated genomics and transcriptomics on 100 small cell cancers from a range of metastatic sites finding complex intra- and intertumoral heterogeneity, notably not recapitulated in patient-derived model systems, and distinct therapeutic vulnerabilities associated with neuroendocrine subtypes.
- Delphine Lissa
- , Nobuyuki Takahashi
- & Anish Thomas
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Article
| Open AccessGenomic and transcriptomic analysis of a library of small cell lung cancer patient-derived xenografts
Creating accurate models of small cell lung cancer is essential to ensure the clinical relevance of results. Here, the authors create patient derived xenograft models from 33 patients and show, through multi-omics sequencing, that these models retain the primary features of the original.
- Rebecca Caeser
- , Jacklynn V. Egger
- & Triparna Sen
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Article
| Open AccessZebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis
It is unclear how a single oncogenic cell primes tumorigenesis. Here the authors visualised this behaviour using a zebrafish larval skin as a model and show that RasG12V oncogenic cell is eliminated through oncogene-senescence while a gain of function mutation in p53 alters this behaviour from tumour suppressive to tumour promoting.
- Yukinari Haraoka
- , Yuki Akieda
- & Tohru Ishitani
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Article
| Open AccessLKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer
LKB1 tumour suppressor gene is frequently mutated in lung adenocarcinoma. Here the authors show that in genetically engineered mouse models of lung cancer Lkb1 restoration induces growth arrest and drives neoplastic cells toward a more differentiated and less proliferative alveolar type II cell-like state via C/EBP-mediated reprogramming.
- Christopher W. Murray
- , Jennifer J. Brady
- & Monte M. Winslow
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Article
| Open AccessAn instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia
Activating mutations in Interleukin-7 receptor alpha (IL7Ra) have been reported in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) but its role in leukaemogenesis is not clear. Here, the authors show that activation of IL7Ra in primary human hematopoietic progenitors initiates preleukaemia and cooperates with CDKN2A silencing to develop BCP-ALL.
- Ifat Geron
- , Angela Maria Savino
- & Shai Izraeli
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Article
| Open AccessPPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation
PPM1D is a known mediator of p53 signalling, and has been linked to treatment resistance in glioma. In this work, the authors utilise genomics, proteomics, and mouse models to determine the role of PPM1D in the development of diffuse midline glioma.
- Prasidda Khadka
- , Zachary J. Reitman
- & Pratiti Bandopadhayay
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Article
| Open AccessRNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state
The E3 ubiquitin ligases RNF43/ZNRF3 are often mutated in cancer but their precise contribution to liver disease is unknown. Here, the authors show that RNF43/ZNRF3 alterations predispose to liver cancer by controlling the differentiation and lipid metabolic state of hepatocytes.
- Germán Belenguer
- , Gianmarco Mastrogiovanni
- & Meritxell Huch
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Article
| Open AccessmolBV reveals immune landscape of bacterial vaginosis and predicts human papillomavirus infection natural history
Here, Burk et al. develop an algorithm to diagnose bacterial vaginosis (BV) using the 16S rRNA gene, called molBV, which they use to profile the inflammatory landscape of BV and predict progression of human papillomavirus infection to cervical pre-cancer.
- Mykhaylo Usyk
- , Nicolas F. Schlecht
- & Robert D. Burk
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Article
| Open AccessSingle-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states
The changes that prostate cancer (PCa) induces in its microenvironment are not fully understood. Here the authors use single-cell RNA-seq and organoids to characterise how the microenvironment responds to PCa, and also identify tumour-associated epithelial cell states and club cells.
- Hanbing Song
- , Hannah N. W. Weinstein
- & Franklin W. Huang
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Article
| Open AccessDecoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α
IRE1 helps mitigate endoplasmic-reticulum stress by cleaving specific mRNAs at a conserved sequence endomotif via regulated IRE1-dependent decay (RIDD). Here the authors discover a more promiscuous IRE1 activity dubbed RIDD lacking endomotif (RIDDLE).
- Adrien Le Thomas
- , Elena Ferri
- & Avi Ashkenazi
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Article
| Open AccessInterleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia
Interleukin-7 receptor alpha (IL7Ra) is important for lymphoid cell development but its role in leukaemogenesis is not clear. Here, the authors generate a knock-in murine model to show that activating mutations in IL7Ra can initiate precursor B-cell acute lymphoblastic leukaemia.
- Afonso R. M. Almeida
- , João L. Neto
- & João T. Barata
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Article
| Open AccessCompressive stress-mediated p38 activation required for ERα + phenotype in breast cancer
Reliable luminal estrogen receptor (ERα+) breast cancer models are limited. Here, the authors use patient derived breast epithelial and breast cancer explant cultures grown in several extracellular matrix scaffolds and show that ERα expression is regulated by matrix stiffness via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation.
- Pauliina M. Munne
- , Lahja Martikainen
- & Juha Klefström
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Article
| Open AccessHigh endogenous CCL2 expression promotes the aggressive phenotype of human inflammatory breast cancer
Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with a poor prognosis. Here the authors report the characterization of a human IBC cell line recapitulating the clinical and histopathological features of the human disease, and implicating its high level of CCL2 in macrophage infiltration and tumor progression.
- Anita Rogic
- , Ila Pant
- & Stuart A. Aaronson
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Article
| Open AccessA tissue-bioengineering strategy for modeling rare human kidney diseases in vivo
The lack of animal models for some human diseases precludes our understanding of disease mechanisms and our ability to test new therapies in vivo. Here the authors present a tissue bioengineering strategy for the study of a rare kidney tumor called angiomyolipoma, in vitro and in vivo, using patient-derived hiPSCs.
- J. O. R. Hernandez
- , X. Wang
- & D. R. Lemos