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Principal Investigator: Diana Chin
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $53,974
Funding agency: National Cancer Institute
PROJECT SUMMARY
Osteosarcoma (OS) metastasis is the leading driver of mortality, but there are no therapies tailored to metastatic
disease. Despite the development of numerous treatment modalities targeting the primary tumor, 40% of pa-
tients still die from metastatic progression. Developing targeted therapies for metastatic OS has been compli-
cated by extensive genomic rearrangements that differ across patients, but a common feature is that OS tends
to metastasize to the lung. There is a pressing clinical need to determine the factors responsible for lung me-
tastasis in OS to facilitate development of novel antimetastatic therapies. Previous findings have demonstrated
the importance of alterations in enhancer activity and specific transcription factors in activating genes necessary
for metastasis. However, recent studies on epigenetic subtypes of OS suggest that many of the models studied
previously diverge from the epigenetic subtype of this disease most common and most deadly in the clinic.
Here we propose in aim 1 to study the transcription factors (RUNX2 and SP7) that are specific to the subtype of
OS that is most clinically relevant, and we plan to characterize how these create: de novo enhancer activation,
novel loops and clusters in cis and trans, and novel enhancer-gene connections that promote lung metastasis.
Our goal is to define “metastasis enabling circuitry”. Aim 2 tests the hypothesis that the process of lung coloni-
zation is driven by an interplay between RUNX2 and signaling from the lung microenvironment through a longi-
tudinal series of dynamic chromatin state changes, each with unique gene dependencies. We seek to understand
the biology of the metastatic process by charting the chromatin state transitions and dependencies in osteosar-
coma cells growing within the in vivo context of the lung microenvironment. If successful, we hope to expand the
current arsenal of OS treatments beyond coverage of the primary lesion, to target tumor metastases during lung
colonization.
Terms: <3-D><3-Dimensional><3D><4C-seq><ATAC sequencing><ATAC-seq><ATACseq><Adolescent><Adolescent Youth><Affect><Assay for Transposase-Accessible Chromatin using sequencing><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding><Biological><Biology><Bone Sarcoma><CRISPR interference><CRISPR-dCas9-mediated repression><CRISPR/dCas9 interference><CRISPR/dCas9-mediated transcriptional inhibition><CRISPRi><Cancers><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cells><Cessation of life><ChIP Sequencing><ChIP-seq><ChIPseq><Chromatin><Chromatin Conformation Capture and Sequencing><Clinic><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats interference><Competence><Complex><Copy Number Polymorphism><DNA Alteration><DNA Sequence Alteration><DNA Sequence Rearrangement><DNA mutation><DNA-Dependent RNA Polymerase II><Data Bases><Databases><Death><Dependence><Development><Diagnosis><Disease><Disorder><Distant><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Family><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic mutation><Genome><Genomics><Genotoxins><Goals><Growth><Harvest><Homeostasis><Human Cell Line><In Vitro><Inflammatory><Injections><Intracellular Communication and Signaling><JV15-2><Knock-in><Label><Lung><Lung Respiratory System><MADH3><MADH3 gene><MADH6><MADH6 gene><MNNG><Malignant Neoplasms><Malignant Tumor><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mesenchymal stromal/stem cells><Metastasis><Metastasis to the Lung><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Lung><Metastatic Osteogenic Sarcoma><Metastatic Osteosarcoma><Metastatic Tumor><Metastatic Tumor to the Lung><Methylnitronitrosoguanidine><Methylnitrosonitroguanidine><Modality><Modeling><Modification><Molecular Interaction><Mothers Against Decapentaplegic, Drosophila, Homolog of, 3><Mutagens><N-Methyl-N'-nitro-N-nitrosoguanidine><N-methyl-N'-nitro-N-nitroso-guanidine><Neoplasm Metastasis><Nitrosomethylnitroguanidine><Nitrosonitromethylguanidine><Osseous Sarcoma><Osteogenic Sarcoma><Osteosarcoma><PDX model><Pathway interactions><Patient derived xenograft><Patients><Physiological Homeostasis><Primary Lesion><Primary Neoplasm><Primary Tumor><Process><Prognosis><Property><Puma><RNA Polymerase B><RNA Polymerase II><RNA Seq><RNA sequencing><RNAseq><Role><SMA- and MAD-Related Protein 3><SMAD3><SMAD6><Secondary Neoplasm><Secondary Tumor><Sequence Alteration><Serial Passage><Series><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skeletal Sarcoma><Strains Cell Lines><Study models><System><Tail><Testing><Time><Tissue Growth><Transcription Factor Proto-Oncogene><Transcription factor genes><Up-Regulation><Upregulation><Veins><Virus><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biologic><biological signal transduction><cancer metastasis><cancer type><chromatin immunoprecipitation-sequencing><clinical relevance><clinically relevant><cohort><colonization associated with lung><colonization in the lung><colonization within the lung><copy number variant><copy number variation><cultured cell line><customized therapy><customized treatment><data base><developmental><disease subgroups><disease subtype><disorder subtype><epigenetically><epigenomics><experiment><experimental research><experimental study><experiments><genomic alteration><genomic rearrangement><genotoxic agent><in vivo><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><inhibitor><juvenile><juvenile human><knockin><lens><lenses><lung colonization><lung metastasis><malignancy><mesenchymal stromal progenitor cells><mesenchymal-derived stem cells><metastasize to the lung><metastatic process><mortality><neoplasm/cancer><novel><ontogeny><osteochondrosarcoma><osteogenic><osteoid sarcoma><pathway><patient derived xenograft model><patient specific therapies><patient specific treatment><primary bone cancer><primary bone tumor><promoter><promotor><pulmonary><pulmonary colonization><pulmonary metastasis><repressing CRISPR-dCas9 system><risk stratification><social role><stratify risk><tailored medical treatment><tailored therapy><tailored treatment><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><three dimensional><tool><transcription factor><transcriptome sequencing><transcriptomic sequencing><tumor><tumor cell metastasis><unique treatment>