Biomedical Sciences ETDs

Publication Date

Fall 12-2019

Abstract

Salivary gland adenoid cystic carcinoma (ACC) is an aggressive tumor with a tendency to infiltrate surrounding nerves and metastasize to distant sites. The standard treatment often fails to control local tumor recurrence and distant metastases and no approved targeted therapeutic options exist for these tumors. The goal of our studies was to reveal the molecular mechanisms driving ACC tumor development and novel drug targets to improve patient morbidity and mortality.

We first analyzed clinical and RNA-sequencing (RNA-seq) data for 68 formalin-fixed paraffin-embedded (FFPE) ACC tumor samples and described previously unappreciated molecular heterogeneity that predicts patient outcome. The poor outcome subgroup had a gene expression signature that resembled embryonic stem cells, suggesting these patients had high-grade dedifferentated tumors. We also utilized these RNA-seq data to definitively show that the MYB and MYBL1 genes are the oncogenic drivers in the vast majority of ACC tumors. ACC tumors that expressed Myb oncogenes were distinct from those that did not, indicating that Myb driven tumorigenesis in ACC tumors results in a unique gene expression pattern. From these analyses we identified and validated the first two high-confidence Myb regulated genes in ACC tumors, the first step in unraveling how Myb driven gene expression changes drive oncogenesis.

The MYB gene must be truncated to unleash its oncogenic potential, in ACC tumors this typically occurs at the C-terminus via chromosomal translocations. However we only observed gene truncation in half of the MYB expressing ACC tumors, raising a new question: how is the oncogenic potential of MYB unleashed in those tumors that appear to express the full-length gene? We found that nearly all of the MYB expressing ACC tumors had an activated alternative MYB gene promoter, which produces N-terminally truncated Myb proteins. Thus, alternative promoter use may unleash the oncogenic potential of the Myb protein in those ACC tumors that appeared to express the non-oncogenic full-length protein. Further investigation revealed significant differences in the gene expression signature elicited by N-terminally truncated Myb isoforms and full-length Myb isoforms. Specifically, N-terminally truncated Myb isoforms uniquely activated a pro-tumorigenic neural migration signaling pathway. A pathway linked to increased perineural invasion, an ACC tumor hallmark associated with poor prognoses. Indeed, we found stratification of ACC tumors by expression of these genes identified a significantly poor outcome subgroup.

The clinical heterogeneity that makes ACC tumors so difficult to treat may be predicted by molecular characterization, thus identifying high-risk patients who are candidates for more aggressive care or personalized therapies. A previously unidentified truncated Myb isoform stimulates perineural invasion, a significant roadblock to curative treatment. These studies have many implications for future studies of the mechanisms of Myb driven tumorigenesis, development of more effective targeted therapeutics, and ultimately patient treatment.

Keywords

MYB, Adenoid Cystic Carcinoma, transcriptomics, semaphorin signaling

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Scott Ness

Second Committee Member

Eric Prossnitz

Third Committee Member

Alan Tomkinson

Fourth Committee Member

Hua-Ying Fan

Fifth Committee Member

David Lee

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