Myc deregulation is a hallmark of cancer and promotes tumor aggression across multiple tumor types. When deregulated, levels of the full length Myc (MYC, MYCN, or MYCL) transcription factor are drastically increased, leading to a global remodeling of gene expression that is poorly understood. Here we show evidence for and propose ?Myc enhancer invasion? as a novel mechanism in which excess Myc protein invades distal cis-regulatory enhancers that are not normally bound at physiological Myc levels. As enhancers control tissue specific gene expression, Myc invasion creates aberrant regulatory interactions that drive tumor progression and can be targeted as a therapeutic strategy. Specifically, we have developed and provide evidence for a model of Myc enhancer invasion in which 1) a subset of enhancers contain weak Myc binding motifs that are accessed when Myc is deregulated. 2) Invaded enhancers act as reservoirs for excess Myc binding and drive the Myc responsive transcription of target genes. 3) Tumor specific enhancer landscapes specify the context of Myc enhancer invasion leading to different enhancer invasion responsive genes in different tumors. 4) Enhancer invaded pathways and other transcription factors that form enhancers can be targeted to interdict tumor specific Myc transcriptional control. To investigate this model for Myc enhancer invasion, we propose the following specific aims. 1) To map and model Myc enhancer invasion in neuroblastoma and osteosarcoma in order to identify genomic parameters that predicate enhancer invasion. 2) To investigate transcriptional consequences of Myc enhancer invasion in vitro and in vivo in order to functionally validate that tumor specific Myc enhancer invaded target genes are dynamically and selectively responsive to Myc perturbation. 3) To identify and target oncogenic Myc enhancer regulation to establish proof of concept for the therapeutic targeting of Myc enhancer regulation. We will perform this work in pediatric neuroblastoma and osteosarcoma models and primary tumors. In these diseases, Myc deregulation is associated with high risk disease, metastasis, increased tumor aggression, and poor responsiveness to existing treatments. As no targeted therapies exist for Myc deregulated neuroblastoma or osteosarcoma, there is a critical unmet need for novel strategies to identify dependencies and effectors of Myc deregulation. In our preliminary data, we find that the enhancer transcription factor TWIST1 acts as a co-factor of MYCN enhancer invasion and is a specific dependency of MYCN driven neuroblastoma. These data highlight the utility of the proposed approach to connect mechanistic investigation of Myc transcriptional regulation to novel frameworks for the identification and validation of tumor specific therapeutic targets in Myc driven neuroblastoma and osteosarcoma.

Public Health Relevance

Our proposal aims to investigate ?Myc enhancer invasion?, a recently observed mechanism in which the oncogenic Myc transcription factor can bind and regulate enhancers, genomic DNA elements that drive tissue specific gene expression. In Myc driven pediatric neuroblastoma and osteosarcoma, we propose an integrated experimental and computational framework to determine why specific enhancers are invaded by Myc and the transcriptional consequences of enhancer invasion in order to understand how Myc enhancer invasion contributes to the often tumor specific consequences of Myc deregulation. We propose that the outputs of Myc enhancer invasion can be therapeutically targeted and will test strategies to identify and inhibit key regulators and effectors of tumor specific Myc enhancer regulation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA215452-01
Application #
9288579
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Mietz, Judy
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$362,569
Indirect Cost
$133,819
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030