Reprogramming chemoresistant cell states in high-risk neuroblastoma - failure of cancer treatments due to the acquired drug resistance poses a challenge for clinician and scientists who are trying…

The National Cancer Institute awarded ST Jude Children's Research Hospital Inc. $143,814 on September 1, 2026, under the Cancer Research Manpower program (CFDA 93.398) to support research training and career development in cancer biology.

The award funds a K99 career transition award (Project Grant K99CA312755) focused on reprogramming chemoresistant cell states in high-risk neuroblastoma. The research addresses acquired drug resistance in pediatric cancer by investigating how neuroblastoma cells transition between epigenetically and transcriptionally controlled cell states—a drug-sensitive differentiated adrenergic state and a drug-resistant mesenchymal state—to evade chemotherapy. The investigator integrated epigenomic and transcriptomic data from over thirty neuroblastoma cell lines to develop a reporter system detecting the drug-resistant state, identified the transcription factor FOSL1 as a driver of mesenchymal state maintenance, and discovered that transient inhibition of histone acetyltransferases EP300/CBP partially reprograms mesenchymal cells to restore chemosensitivity. The project will define FOSL1's role in the high-risk mesenchymal cell state and examine the impact of FOSL1 targeting on mesenchymal-to-chemosensitive reprogramming using in vitro and patient-derived xenograft models.

Performance occurs in Memphis, Tennessee. The project period runs September 1, 2026 through August 31, 2028. The Cancer Research Manpower program provides up to five-year support for biomedical training and career development in basic, clinical, and prevention research aligned with the National Cancer Program.

Reprogramming chemoresistant cell states in high-risk neuroblastoma - failure of cancer treatments due to the acquired drug resistance poses a challenge for clinician and scientists who are trying to create new efficient therapies to cure cancer. Drug resistance in pediatric cancer is driven by their ability to hijack developmental processes that allow cancer cell to transition between different cell states in response to therapies thus evading cell death. Neuroblastoma (NB) is the most common extracranial solid tumor in children. High-risk NB patients have less than 60% survival and no curative options exist for children with relapsed disease. NB characterized by comprising two epigenetically and transcriptionally controlled main cell states; a drug sensitive differentiated adrenergic cell state and a drug resistant less differentiated mesenchymal cell state. Mechanisms that drive the transitions of NB tumor cell between these two cell states to gain drug resistance is poorly understood. Here, i integrated epigenomic and transcriptomic data from more than 30 NB cell line to develop a reporter system that captures and detects the drug-resistant cell state. Using this system, i discovered that the transcription factor (TF) FOSL1 maintains NB cells in the MES state. Further, by combining my cell state reporter with high content image-based small molecule screening, i discovered that transient inhibition of the histone acetyltransferases EP300/CBP partially reprograms MES cells, causing sensitivity to multiple chemotherapies. These data suggest the attractive hypothesis that MES state reprogramming may enhance NB treatment efficacy. In AIM1 of this proposal, i will use these findings to define the role of FOSL1 in maintenance and initiation of the high-risk MES cell state in NB. In parallel, using in vitro and MES patientderived xenograft in vivo models i will examine the impact of targeting of FOSL1 on the reprogramming of MES cells into chemosensitive cell state. In aim 2, based on my findings that EP300/CBP inhibition causes loss of MES gene expression but not gain of adrn state gene expression, and these adrn gene loci retain the PRC2- catalyzed H3K27ME3 repressive mark, i will examine the mechanism by which the PRC2 complex controls the MES cell state in NB. Further, i will examine how targeting of the EP300/CBP and PRC2 complexes influence reprogramming and chemosensitivity in vitro and in vivo. In this proposal using a novel high-risk cell state reporter system, i defined transcriptional and epigenetic proteins as candidates for regulation of cellular plasticity and driving resistance in NB. This proposal will define the mechanisms of cellular plasticity and provide new approaches to drive cell state reprogramming to reverse the resistance to chemotherapy treatments in NB by targeting the transcriptional and epigenetic regulators of cell state. Animal models that will be used in these studies are essential to evaluate tumor cell state plasticity and therapeutic responses within a physiologically relevant microenvironment that cannot be fully recapitulated in vitro or in other nonmammalian systems.