Biology subjects

Nance, S.

Publications and source records attributed to Nance, S..

3 recordsLinked to original sources

bioRxiv2026

Synergistic targeting of EP300/CBP and EYA co-activators collapses the rhabdomyosarcoma core regulatory circuit

Rhabdomyosarcoma (RMS) is a multi-subtype, high-risk pediatric sarcoma with a low mutational burden. The mutations found in RMS often alter genes involved in transcriptional control. Approaches to target dysregulated RMS transcription have remained elusive. Here, we develop a novel approach to target RMS transcription comprising simultaneous targeting of two distinctly acting transcriptional co-activators. We discover a common identity-controlling pan-RMS core regulatory circuit (CRC) composed of oncogenic and lineage-specific myogenic master transcription factors (mTFs). Using a super-enhancer-based reporter screen, we identify the EP300/CBP inhibitor A485 as a potent inhibitor of the pan-RMS CRC, though with efficacy-limiting toxicities. To enhance efficacy, we identify the mTF-binding co-activator EYA2 as a co-factor of this pan-RMS CRC and exploit a new second-generation EYA1/2 inhibitor, LG1-34, to disrupt its function. Combined co-activator inhibition inactivates the CRC and synergistically reduces RMS growth. This strategy dually targets CRC-associated co-activators to cooperatively suppress the RMS transcriptome and enforce cell death.

cancer biology↗

bioRxiv2023

A CRISPR-drug perturbational map for identifying new compounds to combine with commonly used chemotherapeutics.

Combination chemotherapy is crucial for achieving durable cancer cures, however, developing safe and effective drug combinations has been a significant challenge. To improve this process, we conducted large-scale targeted CRISPR knockout screens in drug-treated cells, creating a genetic map of druggable genes that sensitize cells to commonly used chemotherapeutics. We prioritized neuroblastoma, the most common pediatric solid tumor, where 50% of high-risk patients do not survive. Our screen examined all druggable gene knockouts in 18 cell lines (10 neuroblastoma, 8 others) treated with 8 widely used drugs, resulting in 94,320 unique combination-cell line perturbations, which is comparable to the largest drug combination screens ever reported. Remarkably, using dense drug-drug rescreening, we found that the top CRISPR-nominated drug combinations were far more synergistic than standard-of-care combinations, suggesting existing combinations could be improved. As proof of principle, we discovered that inhibition of PRKDC, a component of the non-homologous end-joining pathway, sensitizes high-risk neuroblastoma cells to the standard-of-care drug doxorubicin in vitro and in vivo using PDX models. Our findings provide a valuable resource for the development of improved chemotherapeutic strategies and demonstrate the feasibility of using targeted CRISPR knockout to discover new combinations with common chemotherapeutics, a methodology with application across all cancers.

cancer biology↗

bioRxiv2021

SIX1 is a master regulator of the Rhabdomyosarcoma undifferentiated state

Rhabdomyosarcoma (RMS) is a pediatric skeletal muscle sarcoma characterized by the expression of the myogenic-lineage transcription factors (TF) MYOD1 and MYOG. Despite high expression of these TFs, RMS cells fail to terminally differentiate, suggesting the presence of factors that alter their function. Here, we demonstrate that the developmental TF, SIX1, is highly expressed in RMS and is critical to maintain a muscle progenitor-like state. SIX1 loss induces terminal differentiation of RMS cells into myotube-like cells and dramatically impedes tumor growth in vivo. We show that SIX1 maintains the RMS undifferentiated state by controlling enhancer activity and MYOD1 occupancy at loci more permissive to tumor growth over terminal muscle differentiation. Finally, we demonstrate that a gene signature derived from SIX1 loss correlates with differentiation status in RMS and predicts RMS progression in human disease. Our findings demonstrate a master regulatory role for SIX1 in the repression of RMS differentiation via genome-wide alterations in MYOD1-mediated transcription. HighlightsO_LISIX1 prevents differentiation in RMS while it promotes differentiation during normal development C_LIO_LIFN-RMS are highly dependent on SIX1 for growth in both zebrafish and mouse xenograft models C_LIO_LILoss of SIX1 alters the transcriptional landscape of RMS cells, inducing a growth to differentiation switch C_LIO_LISIX1 knockdown in FN-RMS causes reduced super enhancer-based activity at stem-related genes and enhanced MYOD1 binding to differentiation loci, resulting in the activation of a myogenic differentiation program C_LIO_LIA gene signature derived from SIX1 loss strongly correlates with myogenic differentiation status and is predictive of advanced RMS. C_LI

cancer biology↗