Featured
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Article
| Open AccessSynthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity
PTEN copy number loss is found in 25% of fusion-negative rhabdomyosarcomas (FN-RMS). Here, the authors use a Hedgehog-driven FN-RMS mouse model to show that PTEN loss drives the expression of core transcription factor PAX7 and its transcriptional axis, which determines FN-RMS tumour identity.
- Casey G. Langdon
- , Katherine E. Gadek
- & Mark E. Hatley
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Article
| Open AccessMammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer
Human metaplastic breast cancers (MpBC) are a rare, aggressive subclass of triple-negative breast cancers. Here, the authors show over-expression of histone reader TRIM24 is sufficient to generate tumors with a molecular signature of metabolic dysfunction and EMT in a mouse model of human MpBC.
- Vrutant V. Shah
- , Aundrietta D. Duncan
- & Michelle Craig Barton
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Article
| Open AccessImplantable optical fibers for immunotherapeutics delivery and tumor impedance measurement
Immune checkpoint blockade antibodies have promising clinical applications, but suffer from severe toxicities and moderate response rates. Here the authors present an electrode-embedded, implantable optical fiber device with both local delivery and tumor impedance measurement capabilities to safely elicit durable anti-tumor immunity.
- Ai Lin Chin
- , Shan Jiang
- & Rong Tong
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Article
| Open AccessComprehensive characterization of 536 patient-derived xenograft models prioritizes candidates for targeted treatment
Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.
- Hua Sun
- , Song Cao
- & Li Ding
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Article
| Open AccessThe MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology
The prognosis of castration-resistant prostate cancers remains dismal, but accurate preclinical models can lead to effective therapies. Here the Melbourne Urological Research Alliance establish prostate cancer patient-derived xenografts, use the tumors for organoids and single-cell RNA-seq, and show the efficacy of PARP inhibitor combination treatments.
- Gail P. Risbridger
- , Ashlee K. Clark
- & Renea A. Taylor
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Article
| Open AccessCanine tumor mutational burden is correlated with TP53 mutation across tumor types and breeds
Genomic studies of canine tumours have been done for individual cancer types or dog breeds. Here the authors analyse canine tumour genomics data across multiple breeds and cancer types, finding that mutational burden is associated with TP53 mutations and that Golden Retrievers are enriched for particular signatures.
- Burair A. Alsaihati
- , Kun-Lin Ho
- & Shaying Zhao
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Article
| Open AccessPatient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma
Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response.
- Chen He
- , Ke Xu
- & Suzanne J. Baker
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Article
| Open AccessHighly metastatic claudin-low mammary cancers can originate from luminal epithelial cells
The cellular origin and oncogenic drivers promoting claudin-low breast cancer are undefined. Here, the authors report that the consistent activation of oncogenic RAS signaling, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.
- Patrick D. Rädler
- , Barbara L. Wehde
- & Kay-Uwe Wagner
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Article
| Open AccessOncogenic 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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Article
| Open AccessLung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week
The lengthy time in establishing patient-derived organoids(PDOs) hampers the implementation of PDO-based drug sensitivity tests in clinics. Here, the authors show a microwell array-based method to predict patient’s responses to anti-cancer therapies in a week using lung cancer organoids.
- Yawei Hu
- , Xizhao Sui
- & Peng Liu
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Article
| Open AccessCancer 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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Article
| Open AccessSOD1 regulates ribosome biogenesis in KRAS mutant non-small cell lung cancer
The superoxide dismutase SOD1 is highly expressed in lung cancer but its role has not fully investigated yet. In this study, the authors demonstrate that SOD1 regulates ribosome biogenesis driving KRAS-driven lung tumorigenesis.
- Xiaowen Wang
- , Hong Zhang
- & X. F. Steven Zheng
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Article
| Open AccessLipocalin 2 mediates appetite suppression during pancreatic cancer cachexia
Lipocalin 2 (LCN2) has been recently identified as an endogenous regulator of appetite. Here, using pancreatic cancer as a model of cachexia, the authors demonstrate that LCN2 is a critical mediator of cancer-associated anorexia and may be therapeutically targeted to improve patient outcomes.
- Brennan Olson
- , Xinxia Zhu
- & Daniel L. Marks
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Article
| Open AccessPresence of complete murine viral genome sequences in patient-derived xenografts
Patient-derived xenografts are widely used for drug development, but the impact of murine viral infection remains underexplored. Here, the authors demonstrate the extensive existence of murine viral sequences in patient-derived xenografts and significant expression change of crucial genes in samples with high virus load.
- Zihao Yuan
- , Xuejun Fan
- & W. Jim Zheng
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Article
| Open AccessHOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia
Nucleophosmin (NPM1) gene mutation induces a specific gene expression program leading to acute myeloid leukaemia. Here, the authors show that mutant NPM1 activates a HOXB locus-associated long non-coding RNA which is essential for its associated oncogenic transcriptional program and leukaemia development.
- Ganqian Zhu
- , Huacheng Luo
- & Mingjiang Xu
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Article
| Open AccessSingle-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer
It has been proposed that resistance to targeted therapies in non-small cell lung carcinoma (NSCLC) is due to a nonhomogeneous cell population. Here the authors analyse preclinical NSCLC models using single-cell RNA-seq and identify drug tolerant cell states and subpopulations, as well as associated genes.
- Alexandre F. Aissa
- , Abul B. M. M. K. Islam
- & Elizaveta V. Benevolenskaya
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Article
| Open AccessKRAS drives immune evasion in a genetic model of pancreatic cancer
Oncogenic KRAS signalling is required for tumor initiation; however KRAS-dependency at advanced stages is less understood. Here, the authors show that, in established KRAS-driven pancreatic cancer, KRAS-ablation does not affect intrinsic tumorigenic capacity but elicits antitumor immune response, highlighting the importance of KRAS-driven immune suppression in tumor maintenance.
- Irene Ischenko
- , Stephen D’Amico
- & Nancy C. Reich
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Article
| Open AccessSomatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours
Malignant rhabdoid tumours (MRT) have been suggested to originate in the ectoderm-derived neural crest. Here, the authors analyse MRTs using phylogenetics, scRNA-seq, and patient-derived organoids; they find evidence for an MRT origin in the neural crest lineage and suggest differentiation treatment with HDAC/mTOR inhibitors.
- Lars Custers
- , Eleonora Khabirova
- & Jarno Drost
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Article
| Open AccessPatient-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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Article
| Open AccessMalignant subclone drives metastasis of genetically and phenotypically heterogenous cell clusters through fibrotic niche generation
Cancer cell clusters metastasize to distant organ by polyclonal manner. Here, the authors show that malignant subclone induces fibrotic niche generation in the liver by hepatic stellate cell activation, supporting survival and colonization of non-metastatic cells to develop polyclonal metastasis.
- Sau Yee Kok
- , Hiroko Oshima
- & Masanobu Oshima
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Article
| Open AccessH3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions
Mechanisms underlying gene repression and silencers remain poorly understood. Here the authors investigate the role of H3K27me3-rich regions in the genome, as defined from clusters of H3K27me3 peaks, in regulating gene expression via looping.
- Yichao Cai
- , Ying Zhang
- & Melissa Jane Fullwood
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Article
| Open AccessHyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver
Polyploidy is a common feature in normal hepatocytes, however, the pathophysiological function of hepatic hyperpolyploidy is unclear. Here, the authors show that genotoxic stress induces accumulation of hyperpolyploid hepatocytes around the centrilobular region of the liver, which may indicate the origin of preneoplastic formation.
- Heng Lin
- , Yen-Sung Huang
- & Hsu-Wen Chao
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Article
| Open AccessGlobal computational alignment of tumor and cell line transcriptional profiles
The determination of whether cancer cell lines recapitulate the molecular features of corresponding patient tumours remains essential for the selection of appropriate cell line models for preclinical studies. The method developed here, Celligner, integrates cancer cell line and tumour RNA-seq datasets and reveals large differences in their concordance across cell lines and cancer types.
- Allison Warren
- , Yejia Chen
- & James M. McFarland
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Article
| Open AccessA RAC-GEF network critical for early intestinal tumourigenesis
Loss of small GTPase RAC1 suppresses intestinal tumorigenesis caused by APC loss, but impacts normal intestinal homeostasis. Here, the authors provide an alternative method of reducing RAC1 activity by the combined targeting of three RAC-GEFs and show that this approach delays intestinal tumorigenesis without the detrimental effects on normal intestinal architecture.
- K. A. Pickering
- , K. Gilroy
- & O. J. Sansom
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Article
| Open AccessSingle cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy
Promising results of cancer therapies in transplant tumor models often fail to predict efficacy in clinical trials. Here the authors show that, while transplant tumors are cured by radiotherapy and PD-1 blockade, autochthonous sarcomas are resistant to the identical treatment, recapitulating the immune landscape and resistance to checkpoint blockade observed in most sarcoma patients.
- Amy J. Wisdom
- , Yvonne M. Mowery
- & David G. Kirsch
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Article
| Open AccessEpigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer
Histone H3 at lysine 27 (H3K27M) is often mutated in cancer but its role in tumour initiation is unclear. Here, the authors generated a transgenic model expressing H3.3K27M from the Fabp7 gene promoter, demonstrating that H3.3K27M can initiate diverse tumorigesis on its own, acting through a RAS/MYC transcriptomic programme.
- Sanja Pajovic
- , Robert Siddaway
- & Cynthia Hawkins
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Article
| Open AccessGap junctions amplify spatial variations in cell volume in proliferating tumor spheroids
Cell proliferation is regulated by cell volume, but it is unclear how individual cancer cells coordinate to regulate cell volumes in 3D clusters. Here the authors propose a mechano-osmotic model to analyse the exchange of fluid and ions between connected cells and their environment in response to proliferation-induced solid stress.
- Eoin McEvoy
- , Yu Long Han
- & Vivek B. Shenoy
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Article
| Open AccessCathepsin D deficiency in mammary epithelium transiently stalls breast cancer by interference with mTORC1 signaling
The lysosomal aspartic protease Cathepsin D (CTSD) is associated with breast cancer progression. Here the authors show that selective inactivation of CTSD in mammary epithelium delays tumor onset due to impaired mTORC1 signaling, but resumes malignant growth due to compensatory oncogenic pathways
- Stephanie Ketterer
- , Julia Mitschke
- & Thomas Reinheckel
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Article
| Open AccessCalreticulin del52 and ins5 knock-in mice recapitulate different myeloproliferative phenotypes observed in patients with MPN
Calreticulin del52 and ins5 mutations induce two phenotypically distinct myeloproliferative neoplasms in patients. Here the authors show that modeling these mutations in knock-in mice recapitulate the two diseases and highlight how they impact the different hematopoietic compartments.
- Camélia Benlabiod
- , Maira da Costa Cacemiro
- & Caroline Marty
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Article
| Open AccessVAV2 signaling promotes regenerative proliferation in both cutaneous and head and neck squamous cell carcinoma
The Rho signalling pathway is frequently activated in squamous carcinomas. Here, the authors find that the Rho GEF VAV2 is over expressed in both cutaneous and head and neck squamous cell carcinomas and that at the molecular level VAV2 promotes a pro-tumorigenic stem cell-like signalling programme.
- L. Francisco Lorenzo-Martín
- , Natalia Fernández-Parejo
- & Xosé R. Bustelo
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Article
| Open AccessGlioma-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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Article
| Open AccessA phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis
RNF43 is frequently mutated in cancers and negatively regulates Wnt signalling. Here, the authors report that RNF43 phosphorylation at a serine triplet is required for the negative regulation of Wnt signalling and that the phosphorylation of RNF43 suppresses cancer-associated oncogenic RNF43 mutants.
- Tadasuke Tsukiyama
- , Juqi Zou
- & Shigetsugu Hatakeyama
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Article
| Open AccessPhenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity
Patient-specific precision medicine approaches are important for future cancer therapies. Here, the authors show that functional drug profiling with Rhabdomyosarcoma cells isolated from PDX and primary patient tumors uncovers patient-specific vulnerabilities.
- Gabriele Manzella
- , Leonie D. Schreck
- & Marco Wachtel
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Matters Arising
| Open AccessLinkage of genetic drivers and strain-specific germline variants confound mouse cancer genome analyses
- Sebastian Mueller
- , Sebastian Lange
- & Roland Rad
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Article
| Open AccessHIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice
Genetic inactivation of VHL leads to stabilization of HIF-1α/HIF-2α and is associated with clear cell renal cell carcinoma (ccRCC) initiation and progression. Using an autochthonous mouse model of ccRCC with Vhl deletion, here the authors show that HIF-1α is necessary for tumor formation, while HIF-2α deletion has only a moderate effect.
- Rouven Hoefflin
- , Sabine Harlander
- & Ian J. Frew
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Article
| Open AccessPLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance
Identifying novel therapies for the treatment of CDK4/6 inhibitor-resistant patients is of great importance. Here, the authors demonstrate that PLK1 inhibition is a potential therapeutic target in CCND1-driven and in RB-positive Palbociclib-resistant breast cancers.
- Elodie Montaudon
- , Joanna Nikitorowicz-Buniak
- & Elisabetta Marangoni
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Article
| Open AccessH3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients
Therapy-induced senescence reflects a biological effector principle that is underrecognized in lesion-focused cancer precision medicine. Here the authors utilize mouse lymphoma genetics to functionally dissect senescence and cross-species apply a novel senescence-based prognosticator to lymphoma patients.
- Kolja Schleich
- , Julia Kase
- & Clemens A. Schmitt
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Article
| Open AccessProteome activity landscapes of tumor cell lines determine drug responses
Proteome activity has a major role in cancer progression and response to drugs. Here, the authors use comprehensive proteomic and phosphoproteomic data, in conjunction with drug-sensitivity screens, to generate a community resource consisting of landscapes of pathway and kinase activity across different cell lines
- Martin Frejno
- , Chen Meng
- & Bernhard Kuster
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Review Article
| Open AccessPre-clinical modeling of cutaneous melanoma
Despite the new targeted and immunotherapies for metastatic melanoma, several patients show therapeutic plateau. Here, the authors review the current pre-clinical models of cutaneous melanoma and discuss their strengths and limitations that may help with overcoming therapeutic plateau.
- Vito W. Rebecca
- , Rajasekharan Somasundaram
- & Meenhard Herlyn
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Article
| Open AccessAn essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development
Argonaute 2 (AGO2) binds RAS and is required for cellular transformation. Here, the authors establish a KRAS-driven mouse model of pancreatic cancer with conditional loss of AGO2 and show that the early phase of neoplastic lesion initiation is dependent on EGFR/RAS but not AGO2, while AGO2 is required for pancreatic ductal adenocarcinoma progression and metastasis.
- Sunita Shankar
- , Jean Ching-Yi Tien
- & Arul M. Chinnaiyan
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Article
| Open AccessThe tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture
Conventional co-culture systems often lack physiological complexity of the tumor microenvironment. Here, the authors report an organotypic skin melanoma culture and use this model to investigate the tumor induced suppression on dendritic cells.
- S. Di Blasio
- , G. F. van Wigcheren
- & C. G. Figdor
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Article
| Open AccessChronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation
It is unclear how resident p16-expressing senescent cells affect the propensity of tissues to develop cancer. Here, the authors show that chronic p16 expression in the mouse epidermis causes hyperplasia and dysplasia through Wnt-mediated paracrine stimulation of proliferating keratinocytes, and can contribute to tumour formation.
- Narmen Azazmeh
- , Benjamin Assouline
- & Ittai Ben-Porath
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Article
| Open AccessAssessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids
The relative contribution of fallopian tube (FT) or ovarian surface epithelium (OSE) to high-grade serous ovarian cancer (HG-SOC) development is unclear. Here, the authors establish organoid models from murine oviductal and OSE tissues that allow cancer modeling via CRISPR-Cas9 genome editing, and report a dual origin of murine HG-SOC.
- Kadi Lõhmussaar
- , Oded Kopper
- & Hans Clevers
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Article
| Open AccessYAP1/TAZ drives ependymoma-like tumour formation in mice
YAP1 gene fusions are found in subgroups of paediatric ependymomas. Here the authors show that YAP1 activation in NeuroD6 positive neuronal precursor cells can induce ependymoma-like tumours in mice.
- Noreen Eder
- , Federico Roncaroli
- & Sila K. Ultanir
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Article
| Open AccessSequential Ras/MAPK and PI3K/AKT/mTOR pathways recruitment drives basal extrusion in the prostate-like gland of Drosophila
The molecular mechanisms leading to basal extrusion are unclear. Here, the authors use the Drosophila accessory gland to model human prostate acini and show that Ras/MAPK and PI3K/AKT/mTOR pathways are co-activated in two autocrine loops by dEGF and dIGF, inducing basal extrusion and subsequent tumour formation.
- Amandine Rambur
- , Corinne Lours-Calet
- & Cyrille de Joussineau
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Article
| Open AccessEffective combinatorial immunotherapy for penile squamous cell carcinoma
Penile squamous cell carcinoma (PSCC) is a cancer that is associated with significant mortality. Here, the authors develop a mouse model of PSCC by co-deletion of Smad4 and Apc in the androgen-responsive penile epithelium, and show synergistic efficacy of checkpoint therapy with cabozantinib or celecoxib in their model.
- Tianhe Huang
- , Xi Cheng
- & Xin Lu
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Article
| Open AccessA BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
Senescent cells can influence the tumour microenvironment by secreting immunomodulatory factors and are thus a therapeutic target. Here, the authors identify a compound that degrades BET leading to DNA damage and activation of autophagy and a reduction in tumour growth.
- Masahiro Wakita
- , Akiko Takahashi
- & Eiji Hara
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Article
| Open AccessGenetic characterization of a unique neuroendocrine transdifferentiation prostate circulating tumor cell-derived eXplant model
Better tumor models are needed for the neuroendocrine subtype of castration resistant prostate cancer (CRPC-NE). Here, the authors develop patient-derived model from circulating tumor cells of a CRPC-NE patient, and provide insights on the sequential acquisition of driver gene mutations promoting NE transdifferentiation.
- Vincent Faugeroux
- , Emma Pailler
- & Françoise Farace
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Article
| Open AccessModeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy
Pineoblastoma is a rare pediatric cancer. Here, the authors present inactivation of Rb plus p53 via a WAP-Cre transgene induces metastatic pineoblastoma resembling human disease, and using this model, predict tricyclic antidepressants as a potential therapy for pineoblastoma, supported by their pre-clinical model.
- Philip E. D. Chung
- , Deena M. A. Gendoo
- & Eldad Zacksenhaus