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Principal Investigator: Sourav Bandyopadhyay
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $942,785
Funding agency: National Cancer Institute
PROJECT SUMMARY
Our general strategy is to take advantage of novel tools and methodologies that we have developed
during our first two CTD^2 funding periods– more specifically pioneering and applying CRISPR based
technologies to aid the discovery and characterization of novel cancer targets and their modulators–
using innovative high throughput technologies. Our end goal is to uncover optimal combinations of
targets with the potential to eliminate all cancer cells, despite their clonal heterogeneity and
environmental context. This requires us to better understand tumor biogenesis, namely the
combinations of genes that drive oncogenesis, and tumor heterogeneity which complicates effective
therapeutic treatment.
In this proposal we build upon exciting systems allowing us to quantitate genotypic and phenotypic cell
heterogeneity in cell culture and in vivo. The overall goal is to identify synthetic gene combinations
necessary for clinical resistance and related to inter- and intra-tumor heterogeneity. We hypothesize
that altered cell states such as inflammatory phenotypes and lineage plasticity fuels therapy tolerance
and resistance. We apply single-cell approaches and cutting-edge lineage tracing tools to investigate
the genesis of pathogenic cellular state changes and use genetic screening, computational and
pharmacologic approaches, and clinically relevant in vitro and in vivo tumor models to identify
mechanistically calibrated, specific therapeutic vulnerabilities. These approaches will be applied to two
cancer, lung and breast adenocarcinoma.
Tumor biogenesis and evolution is a challenging area of research, largely due to the complexity of cell
types and behaviors and the combinations of genes that drive cancer types and subtypes is poorly
understood. We have developed next generation GEMMs to interrogate gene combinations that
promote cancer. In this aim, mouse models will be generated that contain combinations of genetic
perturbations of the top 30 TCGA recurrent mutations. These studies will associate the combination of
perturbagens with specific cell states, despite their clonal heterogeneity and cell state and lay a solid
foundation for identifying which combinations of recurrent genes respond to which therapy, thus
helping to stratify patients. This part of the research program focuses on lung cancer as it synergizes
with other components of the proposal. We apply an evolved lineage tracing technology with single
cell RNA-seq readout that lets us follow tumor evolution with unprecedented resolution. These studies
will help us understand how tumor plasticity enables cancers to evade therapeutic challenges. And
importantly, how the loss of tumor suppressor genes or gene combinations, alters the preferred
evolutionary paths a single transformed cell takes to reach aggressive and metastatic states.
Terms: <Anti-Oncogenes><Antioncogenes><Area><Artificial Genes><Automobile Driving><Benign><Biogenesis><Biological><Body Tissues><Breast Adenocarcinoma><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Calibration><Cancer Genes><Cancer Suppressor Genes><Cancer cell line><Cancer-Promoting Gene><Cancers><Cas nuclease technology><Cell Body><Cell Culture Techniques><Cells><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Data><Development><Distal><Drug Targeting><Drug Tolerance><Drug resistance><Emerogenes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Evolution><Exhibits><Fertilization><Foundations><Funding><Gene Combinations><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Screening><Genetic defect><Genotype><Goals><Growth><Heterogeneity><Human><In Vitro><Inflammatory><Intratumoral heterogeneity><Joints><Lung Adenocarcinoma><Malignant><Malignant - descriptor><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mammary adenocarcinoma><Methodology><Modeling><Modern Man><Molecular><Molecular Target><Mutation><Onco-Suppressor Genes><Oncogenes><Oncogenes-Tumor Suppressors><Oncogenesis><Origin of Life><PDX model><Pathogenicity><Pathway interactions><Patient derived xenograft><Phenotype><Phylogenetic Analysis><Phylogenetics><Process><Pulmonary Cancer><Pulmonary malignant Neoplasm><R-Series Research Projects><R01 Mechanism><R01 Program><Reagent><Recessive Oncogenes><Recurrence><Recurrent><Research><Research Grants><Research Project Grants><Research Projects><Resistance><Resolution><Role><Solid><Synthetic Genes><System><Systems Biology><TCGA><Technology><The Cancer Genome Atlas><Therapeutic><Time><Tissue Growth><Tissues><Transforming Genes><Tumor Cell><Tumor Suppressing Genes><Tumor Suppressor Genes><Work><biologic><cancer cell><cancer sub-types><cancer subtypes><cancer type><cell behavior><cell culture><cell cultures><cell transformation><cell type><cellular behavior><clinical relevance><clinical translation><clinically relevant><clinically translatable><developmental><driving><drug resistant><epigenetically><fertilizations><genome mutation><heterogeneity in tumors><high throughput technology><improved><in vivo><innovate><innovation><innovative><insight><intra-tumoral heterogeneity><intratumor heterogeneity><lung cancer><malignancy><mouse model><murine model><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oncosuppressor gene><ontogeny><pathway><patient derived xenograft model><patient stratification><pharmacologic><precancer><precancerous><premalignant><programs><resistance to Drug><resistance to therapy><resistant><resistant to Drug><resistant to therapy><resolutions><response to therapy><response to treatment><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stratified patient><synergism><synthetic biology><therapeutic resistance><therapeutic response><therapeutic target><therapeutically effective><therapy resistant><therapy response><tool><transformed cells><treatment resistance><treatment response><treatment responsiveness><tumor><tumor growth><tumor heterogeneity><tumorigenesis>