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.
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.