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Principal Investigator: CHARLES ROBERTS
Organization: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
Fiscal Year: 2024
Award: $450,446
Funding agency: National Cancer Institute
Project Summary/Abstract:
A role for SWI/SNF complexes in cancer was first suggested when SMARCB1 was identified as
inactivated in virtually all malignant rhabdoid tumor (RT) cases, a highly aggressive pediatric cancer. It is now
clear that mutations in genes encoding subunits of SWI/SNF (BAF) chromatin-remodeling complexes are
frequent, collectively occurring in over 20% of all cancers. Our group established SMARCB1 as a bona fide
and potent tumor suppressor. We later made high-impact discoveries that helped define mechanisms by which
SWI/SNF mutations lead to dysregulated cell proliferation. Our findings suggest a model whereby SWI/SNF-
facilitated control of transcription underlies cellular fate specification, with disruption of this control being the
basis for cancer formation. Our long-term goals are to elucidate the function of SWI/SNF complexes, to
determine how their loss leads to oncogenesis, and to translate this knowledge into novel therapies.
Based on our findings, we hypothesized that loss of SMARCB1, while driving cancer growth, also
creates unique vulnerabilities. To identify such vulnerabilities, we collaborated with the Pediatric Dependencies
Project to perform a rigorous genome-wide CRISPR deletion screen involving 21 RT cell lines compared to
over 800 other cancer cell lines. Notably, rhabdoid tumors are typically diploid and contain few other mutations,
making them a powerful model with which to study the effects of gene deletions. We have now identified and
validated a novel gene that is specifically essential for rhabdoid cell survival from this screen. Our preliminary
data reveal that this gene's product, previously only linked to gene repression, has unanticipated connections
with SWI/SNF and transcriptional activity. We localize this protein to enhancers and promoters of genes bound
by SWI/SNF and hypothesize that this protein performs a key regulatory role in determining whether activating
SWI/SNF complexes or repressive complexes are recruited, thus serving a pivotal role in dictating cell fate.
We previously demonstrated that SWI/SNF and another repressive protein, EZH2, serve antagonistic roles
in chromatin regulation, a discovery that ultimately led to FDA approval of an EZH2 inhibitor (EZH2i) for
SMARCB1-mutant cancers. Despite this success, the mechanisms that control the interplay between these
complexes are poorly understood, as are the mechanisms that underlie resistance to EZH2i in SWI/SNF-mutant
cancers. To establish mechanisms driving drug resistance, we have performed a near genome-wide CRISPR
screen in EZH2 inhibitor-treated RTs. We previously identified NSD1 as a gene that, when inactivated, causes
resistance to EZH2i. Here, we plan to investigate the mechanism of resistance conferred by mutations in a
second chromatin regulatory gene not previously associated with SWI/SNF functions. Together, these
experiments have the potential for broad impact including understanding the roles of these critical chromatin
remodeling complexes in transcriptional control, in transformation, and as potential therapeutic vulnerabilities.
Terms: <Affect><Automobile Driving><BAF47><BAF47 Gene><Binding><Biologic Models><Biological Models><CRISPR><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas system><CRISPR/Cas9 screen><Cancer cell line><Cancers><Cell Body><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Survival><Cell Viability><Cells><Cellular Proliferation><Childhood><Childhood Cancers><Chromatin><Chromatin Remodeling Complex><Chromatin Remodeling Factor><Clustered Regularly Interspaced Short Palindromic Repeats><Collaborations><Complex><D25 protein><Data><Deacetylase><Dependence><Diploid><Diploidy><Drosophila Liz protein><Drosophila U1 snRNP protein A><Drosophila U1-A protein><Drosophila sans fille protein><Drosophila simply not fertile protein><Drosophila snf protein><Drosophila splicing necessary factor protein><Drug resistance><ENX-1><EZH1><EZH2><EZH2 gene><Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><FDA approved><Family member><Frequencies><Funding><Gene Deletion><Gene Down-Regulation><Gene Expression><Gene Inactivation><Gene Silencing><Gene Transcription><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Glues><Goals><Grant><Growth><Heterograft><Heterologous Transplantation><Human><INI1><INI1 Gene><In vivo analysis><KMT6><KMT6A><Knowledge><Lead><Link><Malignant><Malignant - descriptor><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Neoplasms><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant Soft Tissue Neoplasm><Malignant Tumor><Malignant childhood cancer><Maps><Mating Type Switching/Sucrose Nonfermenting Protein><Model System><Modeling><Modern Man><Molecular><Molecular Interaction><Molecular Tumor Suppression><Mutate><Mutation><Oncogenesis><Pb element><Polycomb><Proteins><RNA Expression><Recurrence><Recurrent><Regulation><Regulator Genes><Resistance><Rhabdoid Cell><Rhabdoid Sarcoma><Rhabdoid Tumor><Role><SMARCB1><SMARCB1 gene><SNF protein><SNF5><SNF5 Gene><SNF5L1><SNF5L1 Gene><SWI/SNF Complex><SWI/SNF Family Complex><SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily B, Member 1 Gene><Sarcoma><Specific qualifier value><Specified><Structure><System><Testing><Therapeutic><Tissue Growth><Transcription><Transcription Activation><Transcription Regulation><Transcription Repression><Transcriptional Activation><Transcriptional Control><Transcriptional Regulation><Transcriptional Regulatory Elements><Transcriptional Repression><Translating><Tumor Cell><Tumor Cell Line><Tumor Suppression><Tumor Suppressor Proteins><Work><Xenograft><Xenograft procedure><Xenotransplantation><cancer cell genome><cancer genome><cancer in a child><cancer in children><child with cancer><childhood malignancy><chromatin modifier><clustered regularly interspaced short palindromic repeats screen><design><designing><driving><drug resistant><epigenetically><experiment><experimental research><experimental study><experiments><gene deletion mutation><gene function><gene product><gene repression><genome mutation><genome scale><genome-wide><genomewide><hSNF5/INI1 Gene><heavy metal Pb><heavy metal lead><in vivo evaluation><in vivo testing><inhibitor><insight><interest><malignancy><malignant soft tissue tumor><mutant><neoplasm/cancer><neoplastic cell><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><ontogeny><pediatric><pediatric cancer><pediatric malignancy><programs><promoter><promotor><recruit><regulatory gene><resistance mechanism><resistance to Drug><resistance to therapy><resistant><resistant mechanism><resistant to Drug><resistant to therapy><social role><success><therapeutic resistance><therapy resistant><trans acting element><transcriptional silencing><treatment resistance><tumor genome><tumor suppressor><tumorigenesis><virtual><xeno-transplant><xeno-transplantation>