Featured
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| Open AccessComprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation
The benefit of hyperthermic intraperitoneal chemotherapy in epithelial ovarian cancer remains controversial. Here, the authors perform a multi-omics analysis of hyperthermia-treated ovarian cancer cells, show that CDK1 becomes hyperactivated and regulates signalling upon hyperthermia, and identify WEE1 as a synergistic therapeutic target for hyperthermic intraperitoneal therapy.
- Xiaohang Yang
- , Xingyuan Hu
- & Chaoyang Sun
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Article
| Open AccessCRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression
The molecular basis of the metastatic disease in prostate cancer remains poorly characterised. Here, the authors investigate the interaction of tumor suppressor and epigenetic factor genes and highlight the role of Kmt2c deficiency in facilitating lung metastasis.
- Huiqiang Cai
- , Bin Zhang
- & Martin K. Thomsen
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Article
| Open AccessExosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma
The behavior of exosomes in vivo is not completely elucidated. Here the authors develop a genetically engineered mouse model (ExoBow) to trace the distribution of exosomes, showing local and inter-organ communication networks, either specific or shared between healthy pancreas and pancreatic ductal adenocarcinoma.
- Bárbara Adem
- , Nuno Bastos
- & Sonia A. Melo
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| Open AccessTumor histoculture captures the dynamic interactions between tumor and immune components in response to anti-PD1 in head and neck cancer
Tumor histocultures have been exploited as tools to predict response to cancer therapy. Here the authors report the development and testing of a tumor histoculture platform to study response to immune checkpoint inhibitors in head and neck squamous cell carcinoma.
- Nandini Pal Basak
- , Kowshik Jaganathan
- & Satish Sankaran
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Article
| Open AccessExperimental evidence for cancer resistance in a bat species
Bats have been suggested to be resistant to cancer due to mechanisms related to their evolved longevity, but the associated molecular drivers are still understudied. Here, the authors examine cancer resistance mechanisms across seven bat species using in vitro and in vivo models, and identify HIF1A, COPS5, and RPS3 as related genes.
- Rong Hua
- , Yuan-Shuo Ma
- & Zhen Liu
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Article
| Open AccessTissue-location-specific transcription programs drive tumor dependencies in colon cancer
Cancers of the same tissue type are characterized with different molecular features depending on anatomical location. Here, the authors show that proximal and distal colon stem cells have distinct transcriptional programs mediated by the transcription factor CDX2, with differential roles in colon cancers based on anatomical location.
- Lijing Yang
- , Lei Tu
- & Hariharan Easwaran
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Article
| Open AccessAndrogen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation
The molecular mechanisms underlying Double-Null Prostate Cancer (DNPC) pathogenesis remain elusive. Here, the authors show that co-activation of HGF/MET and Wnt/β-catenin signaling in mouse prostates results in DNPC-like tumor lesions with elevated expression of XPO1 and ribosomal proteins.
- Won Kyung Kim
- , Alyssa J. Buckley
- & Zijie Sun
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Article
| Open AccessAneuploid embryonic stem cells drive teratoma metastasis
Aneuploidy is associated with cancer metastasis, but the causal relationship between them is unclear. Here the authors show that aneuploid murine embryonic stem cells lead to teratomas that can spread to multiple organs without requiring additional driver gene mutations and identify unique cell populations with high stemness in aneuploid teratomas.
- Rong Xiao
- , Deshu Xu
- & Yue Huang
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Article
| Open AccessReconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset
The cellular origin of human pancreatic ductal adenocarcinoma (PDAC) is still unclear. Here the authors used human primary acinar and ductal cells to successfully reconstitute PDAC tumorigenesis from both lineages and revealed transcriptional changes during early PDAC progression.
- Yi Xu
- , Michael H. Nipper
- & Pei Wang
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Article
| Open AccessLeukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice
Cancer cachexia is a systemic syndrome characterized by dramatic weight loss and decline in adipose tissue and skeletal muscle mass. Here, the authors show that overexpression of leukemia inhibitory factor (LIF), a secreted cytokine, suppresses de novo lipogenesis and induces cachexia in mice.
- Xue Yang
- , Jianming Wang
- & Wenwei Hu
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Article
| Open AccessKRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo
The function of wild-type KRAS in KRAS mutant cancers remains to be explored. Here, the authors show that deletion of the tumour-suppressive wild-type Kras in a KRASG12D driven colon cancer model exacerbates tumour initiation in a MAPK dependent manner, while acting to suppress metastasis through impaired immune suppression.
- Arafath K. Najumudeen
- , Sigrid K. Fey
- & Owen J. Sansom
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Article
| Open AccessMapping and modeling human colorectal carcinoma interactions with the tumor microenvironment
Tumour-microenvironment interactions, pivotal in cancer progression, are challenging to replicate in vitro. Here, the authors use single-cell RNA-seq to analyse these interactions in colorectal cancer within organoid models, and aim to emulate and understand these crucial interactions by introducing specific microenvironmental components.
- Ning Li
- , Qin Zhu
- & Christopher J. Lengner
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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 AccessGenomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer
Subcutaneous patient-derived xenografts are a common tool in cancer research. Here, the authors compare 65 paired early passage xenografts to their original paediatric tumour and show clonal evolution determines seeding of the xenograft.
- Funan He
- , Abhik M. Bandyopadhyay
- & Siyuan Zheng
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Article
| Open AccessComprehensive analysis reveals potential therapeutic targets and an integrated risk stratification model for solitary fibrous tumors
Solitary fibrous tumours are mesenchymal tumours with an unpredictable progression and current medical treatments for relapsed SFTs remain ineffective. Here, the authors identified potential therapeutic targets and risk factors for SFTs and created an integrated risk model using 101 patients, and validated in 3 independent cohorts to successfully predict tumour progression.
- Renjing Zhang
- , Yang Yang
- & Ziming Du
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Article
| Open AccessGenomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype
Breast cancer leptomeningeal metastasis is difficult to assess due to the site. Here, the authors assess cerebrospinal fluid cell-free DNA to show specific mutations present in leptomeningeal metastasis, and develop organoids of the disease.
- Amanda Fitzpatrick
- , Marjan Iravani
- & Clare M. Isacke
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Article
| Open AccessSND1 binds to ERG and promotes tumor growth in genetic mouse models of prostate cancer
The ETS family transcription factor ERG is frequently overexpressed in prostate cancer and known to have a role in carcinogenesis, however, the underlying mechanism is less understood. Here, the authors report an interaction between ERG and SND1 as necessary for ERG-driven prostate cancer initiation using preclinical models.
- Sheng-You Liao
- , Dmytro Rudoy
- & Valeri Vasioukhin
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Article
| Open AccessWnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway
The relevance of cell competition in intestinal epithelial carcinogenesis remains to be explored. Here, the authors find aberrant Wnt activation in RasV12-transformed cells reverses the directionality of cell extrusion mediated by cell competition in intestinal epithelium, causing infiltration into basal lamina rather than apical elimination of transformed cells and consequent development of invasive carcinomas.
- Kazuki Nakai
- , Hancheng Lin
- & Shunsuke Kon
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Article
| Open AccessCathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation
Bile duct tumor thrombosis (BDTT) is a complication associated with advanced hepatocellular carcinoma (HCC) which can severely limits quality of life. Here, the authors develop a spontaneous BDTT mouse model to investigate the cellular original and mechanism underlying the formation of BDTT.
- Lei-Bo Xu
- , Yu-Fei Qin
- & Ping-Pui Wong
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Article
| Open AccessReconstructing disease dynamics for mechanistic insights and clinical benefit
Understanding disease progression dynamics is critical for diagnostics and treatment, but capturing dynamics is difficult. Here, the authors present a method for modelling disease progression from high dimensional molecular data that enables patient stratification and high-risk disease state identification, showcased in bladder cancer.
- Amit Frishberg
- , Neta Milman
- & Shai S. Shen-Orr
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Article
| Open AccessSleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development
Chronic inflammation promotes the development and progression of colorectal cancer (CRC) while the underlying mechanism remains to be elucidated. Here, the authors perform in vivo transposon mutagenesis screening to identify that TNFα-activated senescence signaling acts as selective pressure to drive mutation of Cdkn2a and other senescence-related genes in inflammation-accelerated CRC.
- Kana Shimomura
- , Naoko Hattori
- & Haruna Takeda
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Article
| Open AccessOncogenic context shapes the fitness landscape of tumor suppression
Alterations in oncogenes and tumor suppressor genes are a hallmark of cancer, yet how they interact remains poorly understood. Here, the authors describe a quantitative functional cancer genomics platform in genetically engineered mice, and uncover complex interactions between tumor suppressors and KRAS, BRAF, and EGFR oncogenes across more than 100 different lung tumor genotypes.
- Lily M. Blair
- , Joseph M. Juan
- & Ian P. Winters
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Article
| Open AccessEcological network analysis reveals cancer-dependent chaperone-client interaction structure and robustness
How the cancer environment alters protein interactions is an open question. Galai et al. find a hierarchical pattern whereby cancer type modulates chaperone-client interactions, and they identify structures affecting cancer-specific responses to chaperone loss.
- Geut Galai
- , Xie He
- & Shai Pilosof
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| Open AccessBreaking barriers for glioblastoma with a path to enhanced drug delivery
Progress in treatment for glioblastoma is hindered by the blood-brain barrier (BBB). In genetic mouse models recapitulating brain invasion and abnormal angiogenesis of human glioblastoma, Cai and colleagues demonstrate that optical modulation of the BBB with nanoparticles boosts intratumoural chemotherapy concentration, prolonging survival. We discuss prospects for clinical translation of exemplary innovative techniques.
- Imran Noorani
- & Jorge de la Rosa
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Article
| Open AccessStromal heterogeneity may explain increased incidence of metaplastic breast cancer in women of African descent
Breast cancer patients of African ancestry face worse clinical outcomes, so understanding related cellular and molecular features remains critical. Here, the authors show that stromal cells that are particularly enriched in breast cancer patients with African ancestry can trans-differentiate into different lineages and can be transformed into metaplastic carcinoma.
- Brijesh Kumar
- , Aditi S. Khatpe
- & Harikrishna Nakshatri
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Article
| Open AccessMYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer
Few mouse models recapitulate the complexity of triple negative breast cancer (TNBC). Here, the authors develop and characterise a TNBC mouse model harbouring two common TNBC mutations: amplification of the oncogene MYC and deletion of the tumour suppressor PTEN.
- Zinab O. Doha
- , Xiaoyan Wang
- & Rosalie C. Sears
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Article
| Open AccessSystematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation
During preclinical drug development, the ability of cancer cell lines to faithfully model human disease is important for identifying potential therapeutic strategies. Here, using transcriptomic datasets of over 1000 cell lines, the authors evaluate how representative each line is of its cancer type and present their cell line selection tool.
- Han Jin
- , Cheng Zhang
- & Adil Mardinoglu
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Article
| Open AccessDriver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression
The process by which actinic keratosis differentiates to malignant invasive cutaneous squamous cell carcinoma is unclear. Here, the authors use RNA-seq to illustrate a disease continuum between the two states, and use in vivo models to confirm the role of Tgfbr2, Trp53, and Notch1 in this process.
- Peter Bailey
- , Rachel A. Ridgway
- & Gareth J. Inman
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| Open AccessAn ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress
How cancer cells develop and emerge has long been a matter of debate. Here, the authors reveal a crucial role of ATR-PrimPol in enabling precancerous cells to survive KRASinduced replication stress and expand clonally with genomic instability.
- Taichi Igarashi
- , Marianne Mazevet
- & Bunsyo Shiotani
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Article
| Open AccessOne-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids
CRISPR base editing technologies can be used for disease modelling. Here the authors use various base editing tools to generate tumour models in human adult stem cell-derived hepatocyte, endometrial and intestinal organoids.
- Maarten H. Geurts
- , Shashank Gandhi
- & Hans Clevers
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Article
| Open AccessOptical blood-brain-tumor barrier modulation expands therapeutic options for glioblastoma treatment
Relevant preclinical models and effective drug delivery strategies are important to advance glioblastoma (GBM) therapy. Here, the authors characterise genetically engineered mouse models that recapitulate two important GBM subtypes, and use them to show that picosecond laser stimulation of vascular-targeting gold nanoparticles can modulate blood-brain-tumour barrier permeability and expand therapeutic options for GBM.
- Qi Cai
- , Xiaoqing Li
- & Zhenpeng Qin
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Article
| Open AccessA synthetic metastatic niche reveals antitumor neutrophils drive breast cancer metastatic dormancy in the lungs
3D scaffolds can be used to recapitulate key aspects of the microenvironment of primary tumors and metastatic organs. Here the authors use subcutaneous porous 3D scaffold implants as a tool to study the immune signals in the lungs of metastatic breast cancer, revealing multifaceted roles of neutrophils in regulating lung metastasis.
- Jing Wang
- , Ramon Ocadiz-Ruiz
- & Lonnie D. Shea
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| Open AccessDistinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer
Distinguishing the drivers of metastasis versus those of the primary tumour in breast cancer remains challenging. Here, the authors explore primary-only, metastatic-only, and shared drivers in breast cancer using mammary-specific transposon mutagenesis screens, which leads to potential therapeutic targets to prevent metastasis.
- Zhe Jiang
- , YoungJun Ju
- & Eldad Zacksenhaus
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Article
| Open AccessGenome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma
The availability of relevant animal models that can recapitulate high-risk hepatoblastoma will help to better understand its pathogenesis. Here the authors report and characterize a hepatocyte-specific, MYC-driven hepatoblastoma mouse model and show it recapitulates the human hepatoblastoma pathophysiology.
- Jie Fang
- , Shivendra Singh
- & Jun Yang
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Article
| Open AccessA landscape of response to drug combinations in non-small cell lung cancer
Combination of drugs within cancer treatment is a popular way to overcome resistance and increase efficacy. Here, the authors analyse over 5000 targeted agent combinations in non-small cell lung cancer to identify potentially effective drug strategies.
- Nishanth Ulhas Nair
- , Patricia Greninger
- & Cyril H. Benes
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Article
| Open AccessJoint inference of exclusivity patterns and recurrent trajectories from tumor mutation trees
Understanding cancer evolution is crucial for developing effective therapies. Here, authors present TreeMHN, a probabilistic model for inferring exclusivity patterns of genomic events and evolutionary trajectories from intra-tumor phylogenetic trees.
- Xiang Ge Luo
- , Jack Kuipers
- & Niko Beerenwinkel
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Article
| Open AccessAnalysis and modeling of cancer drug responses using cell cycle phase-specific rate effects
Understanding the impact of anti-cancer therapies on cell cycle progression could contribute to the discovery of effective therapeutic treatments. Here, the authors use genetically engineered breast cancer cell lines and computational models to analyse drug effects on specific cell cycle phases and identify effective combination treatments.
- Sean M. Gross
- , Farnaz Mohammadi
- & Laura M. Heiser
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Article
| Open AccessDrug screening at single-organoid resolution via bioprinting and interferometry
Traditional 2D cell culture platforms do not accurately reflect the physiology of human tumors. Here, authors combine bioprinting and high-speed live cell interferometry with machine learning to measure drug sensitivity at single-organoid resolution in a label-free manner.
- Peyton J. Tebon
- , Bowen Wang
- & Alice Soragni
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Article
| Open AccessLipid droplets are a metabolic vulnerability in melanoma
Lipid droplets are a dynamic organelle found in a variety of cell types, most prominently in adipocytes. Here, the authors find in zebrafish and human cells that lipid droplets are enriched in a subset of melanoma cells that promote cancer formation and growth.
- Dianne Lumaquin-Yin
- , Emily Montal
- & Richard M. White
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Article
| Open AccessmacroH2A2 antagonizes epigenetic programs of stemness in glioblastoma
Self-renewing cells play an important role in initiation, progression, and therapy resistance in glioblastoma. Here, the authors identify histone variant macroH2A2 as a regulator of chromatin organisation resulting in the suppression of transcriptional programs of self-renewal in glioblastoma.
- Ana Nikolic
- , Francesca Maule
- & Marco Gallo
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Article
| Open AccessASPSCR1::TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma
The mechanisms of angiogenesis in alveolar soft part sarcoma (ASPS) remain to be explored. Here, the authors highlight the role of the ASPSCR1::TFE3 fusion in regulating super-enhancer activity during the angiogenic process in ASPS.
- Miwa Tanaka
- , Surachada Chuaychob
- & Takuro Nakamura
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Article
| Open AccessThe molecular and functional landscape of resistance to immune checkpoint blockade in melanoma
Immunotherapy resistance is common among melanoma patients. Here, the authors identify three resistance mechanism subtypes across tumor-derived cell lines and matched samples and highlight antigen presentation disruption as a key mediator of resistance.
- Su Yin Lim
- , Elena Shklovskaya
- & Helen Rizos
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Article
| Open AccessNon-canonical functions of SNAIL drive context-specific cancer progression
SNAIL promotes tumour metastasis through inducing epithelial to mesenchymal transition (EMT). Here the authors report that SNAIL bypasses senescence and regulates cell cycle progression to promote pancreatic carcinogenesis and this is independent of EMT induction.
- Mariel C. Paul
- , Christian Schneeweis
- & Dieter Saur
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Article
| Open AccessSpatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas
The spatial organisation of diffuse midline glioma-H3K27M mutant (DMG) and glioblastoma (GBM) remains to be investigated. Here, the authors integrate short-read and long-read spatial profiling of DMG and GBM to identify regulatory programs and cellular ecosystems in distinct glioma niches.
- Yanming Ren
- , Zongyao Huang
- & Yuan Wang
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Article
| 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