Alternative Splicing Driven by MYCN Activates RAS-MAPK in Neuroblastoma
High-risk neuroblastoma is generally lethal. Children with this cancer are categorized as high risk because drugs in current use fail. Most high-risk tumors shrink in response to therapy, but then grow back and are resistant to subsequent therapies. This proposal addresses a potential mechanism allowing high-risk tumors to grow back and a translatable approach to block this process. A central dogma in biology is that DNA generates RNA and RNA generates protein. RNA is made initially as a long molecule that is subsequently spliced to a mature template for protein synthesis. We show that MYCN, a gene that drives neuroblastoma in half of high-risk patients, activates a gene called TIAL1 that regulates RNA splicing.
We hypothesize that MYCN-regulation of TIAL1 changes the RNA splicing of many genes, and through this regulation, drives high-risk neuroblastoma. One way TIAL1 may do this is by changing the splicing of RNAs to increase the activity of a pathway called MAP-kinase. At relapse, most high-risk neuroblastoma drive MAP-kinase, likely contributing to both relapse and therapy resistance. We have data that TIAL1 drives low-level flux through the MAP-kinase pathway, which we think sets the stage for relapse, by selecting for therapy-resistant tumors with high-level flux. Because inhibitors of MAP-kinase signaling are in clinical use, we further hypothesize that adding such agents to chemotherapy upfront will decrease emergent resistance. We will test these ideas in neuroblastoma cells and in murine models. Successful completion provides the preclinical rationale to move this approach into clinical trials.
Project Update - June 2020
More than half of patients with high-risk neuroblastoma shows activation of MYCN (45%) or MYC (10%). When tumors in high-risk patients recur, these recurrences are typically driven by signaling through a pathway called RAS-MAPK, a pathway not known to be associated with MYC proteins. Our results are significant because we identify TIAL1 and TIA1 as targets of MYCN and MYC, linking these targets to activation of RAS-MAPK signaling and therapy resistance. We hypothesize that flux through this pathway (MYCN/MYC-TIA1/TIAL1-RAS-MAPK) leads to a reservoir of cells resistant to primary therapy, that can drive recurrence.