The National Cancer Institute Oncology Models Forum (NCI OMF) fills an important need for the diverse cancer research communities who use various genetically engineered, transplantation, induced, and spontaneous mammalian models. The NCI OMF will work with the community to evolve comprehensive information resources to guide generating, validating, and credentialing of new models, informing their practical uses, advancing modeling technologies, software tools, catalogs and other resources. The NCI OMF is also committed to fostering collaborations that ensure effective, dependable translational use of various mammalian species and cell-based models, and open sharing of data that are generated from these models.
Oncopig primary hepatocyte (pPH) cell lines from three Oncopigs were cultured and transformed (pHCC) by exposure to AdCre in vitro, resulting in expression of mutant KRAS:G12D and TP53:R167H transgenes in pHCC but not pPH cells. Master regulators of gene expression were conserved across Oncopig and 18 human HCC cell lines. pHCC injection into SCID mice resulted in tumors recapitulating human HCC characteristics. Finally, autologous injection of pHCC cells subcutaneously yielded a tumor histologically characterized as Edmondson Steiner grade 2 HCC with trabecular patterning and T-lymphocyte infiltration. These data demonstrate the Oncopig HCC model's utility for improving detection, treatment, and biomarker discovery relevant to human HCC.
PubMed ID: 28969016
BarkBase, a canine epigenomic resource available at barkbase.org. Samples were collected from a total of six embryos, and six adult dogs. BarkBase hosts data for 27 adult tissue types, with biological replicates, and for one sample of up to five tissues sampled at each of four carefully staged embryonic time points. RNA sequencing is complemented with whole genome sequencing and with assay for transposase-accessible chromatin using sequencing (ATAC-seq), which identifies open chromatin regions. BarkBase introduces a powerful new resource to support comparative studies in dogs and humans.
PubMed ID: 31181663
By the end of treatment (Gardasil-9 is a VLP (emptyviral particle), all tumors, not only those that had been injected, showed complete and durable regression with no local or distant tumor recurrence in the 18-month period of follow up, thus implicating a systemic and/or immune-mediated effect.
PubMed ID: 30906919
By studying clonal evolution of tumor cells derived from human pancreatic tumors, the group demonstrates that in vitro cultures and in vivo tumors are maintained by a common set of tumorigenic cells that can be used to establish clonal replica tumors (CRTs), large cohorts of animals bearing human tumors with identical clonal composition. Using CRTs to conduct quantitative assessments of adaptive responses to therapeutics, The group associated transcriptional landscapes, instead of mutation profiles, with sensitivity or resistance of pancreatic tumors. The paper identified a molecular signature of 200 genes that enables the detection of pre-existing resistant populations of cells in pre-treated tumors and allows the prognostic stratification of PDAC patients in terms of disease-free and overall survival in The Cancer Genome Atlas (TCGA) dataset.
PubMed ID: 30726735
The group genomically characterized 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine the understanding of relapsed disease. In addition, The expression signatures are able to classify tumors for TP53 and NF1 pathway inactivation.
PubMed ID: 31693904
This study showed a tumor-intrinsic mechanism that excludes T cells from the vicinity of tumor cells. They showed that a receptor tyrosine kinase, ephrin-A receptor 2 (EPHA2), regulates prostaglandin endoperoxide synthase 2 (PTGS2) (encodes COX-2) expression in a TGF-β signaling–dependent manner. Genetic ablation of Epha2 or Ptgs2 in preclinical models or pharmacological inhibition of COX-2 elicited the transformation of this immunosuppressive microenvironment into a T cell–permissive milieu. Consequent T cell relocation rendered this immunoresistant malignancy responsive to combinations of checkpoint blockers and CD40 agonists.
PubMed ID: 31355777
The molecular mechanism of microglial associated optic glioma is still unknown. To identify potential tumor-associated microglial factors, global RNAseq gene expression experiment was conducted in the mouse glioma models. After validating of prioritized potential secreted or membrane-bound proteins, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. Some positive effects of targeted Ccl5 in vito and vivo experiments establish Ccl5 a s a relevant stroma-targeted low-grade brain tumor treatment marker
To understand the molecular mechanism of lung cancer metastatic, we combined tumor barcoding in a mouse model of human lung adenocarcinoma with unbiased genomic approaches to identify a transcriptional program that confers metastatic ability and predicts patient survival. Small-scale in vivo screening identified several genes, including Cd109, that encode novel pro-metastatic factors. We uncovered signaling mediated by Janus kinases (Jaks) and the transcription factor Stat3 as a critical, pharmacologically targetable effector of CD109-driven lung cancer metastasis. In summary, by coupling the systematic genomic analysis of purified cancer cells in distinct malignant states from mouse models with extensive human validation, we uncovered several key regulators of metastatic ability, including an actionable pro-metastatic CD109–Jak–Stat3 axis
The factors involved in metastatic lesions remain poorly understand. The study show that 1) high expression of ARNTL2 predicts poor lung adenocarcinoma patient outcome,2) Arntl2 is required for metastatic ability in vivo and clonal growth in cell culture,3) An Arntl2-driven pro-metastatic secretome controls metastatic self-sufficiency,4) Smoc2 is an Arntl2/Clock-dependent pro-metastatic secreted factor. These findings shed light on the molecular mechanisms that enable single cancer cells to form allochthonous tumors in foreign tissue environments
The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally suppressed using a doxycycline-regulated shRNA. Apc suppression produces adenomas in both the small intestine and colon that, in the presence of Kras and p53 mutations, can progress to invasive carcinoma. In established tumors, Apc restoration drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. Tumor regression is accompanied by the re-establishment of normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal and multi-lineage differentiation capability. Our study reveals that CRC cells can revert to functioning normal cells given appropriate signals, and provide compelling in vivo validation of the Wnt pathway as a therapeutic target for treatment of CRC.
Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis, but the molecular mechnism of the double-mutant is unknown. By using a rapid mouse model of FLT3/DNMT3A-Mutant AML and advanced global scRNAseq and methylation profiling techniques, the study demonstrates that DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3 ITD-mutant myeloproliferative neoplasm into AML.
Mechanistic study of immunotherapy resistance in targeted immune checkpoint (anti-PD-1) therapy in two fully immunocompetent mouse models of lung adenocarcinoma: KRAS mice and EGFR-TL mice. Observed upregulated Tim-3 in PD-1 antibody bound T cells of resistant state, and a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
Gliomas are diverse neoplasms with multiple molecular subtypes. How tumor-initiating mutations relate to molecular subtypes as these tumors evolve during malignant progression remains unclear. We used genetically-engineered mouse models, histopathology, genetic lineage tracing, expression profiling, and copy number analyses to examine how genomic tumor diversity evolves during the course of malignant progression from low-to high-grade disease.
A systems approach reveals that engagement of systemic immunity is critical to the process of tumor rejection following immunotherapy. To systematically characterizing diverse cell subsets and their activation states simultaneously under different treatment conditions in a spontaneous mouse model of triple-negative breast cancer, we developed intuitive models for visualizing single-cell data (mass CyTOF)with statistical inference and conducting validations on the hypothesis generated from the global analysis results.