Cancer models

  • Article
    | Open Access

    Current methods for acquiring dissemination kinetics of rare circulating tumor cells (CTCs) that form metastases have several limitations. Here, the authors show an approach for measuring endogenous CTC kinetics by continuously exchanging CTC-containing blood between un-anesthetized, tumor-bearing mice and healthy, tumor-free counterparts.

    • Bashar Hamza
    • , Alex B. Miller
    •  & Scott R. Manalis
  • Article
    | Open Access

    Personalized cancer medicine currently lacks custom platforms that mimic the microenvironment of human tissues. Here, the authors show how self-assembled patient-derived models of pancreatic cancer recapitulate key biological features of the original tumours such as matrix composition and stemness.

    • David Osuna de la Peña
    • , Sara Maria David Trabulo
    •  & Daniela Loessner
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Review Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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