Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology

Summary
Mucoepidermoid carcinomas (MEC) are the most common type of malignant salivary gland tumor (SGT) with
advanced MEC often being fatal due to resistance to conventional therapies. Despite their prevalence in
salivary malignancies and occurrence in other tissues throughout the body, a thorough understanding of the
key molecular events leading to their development has not been fully elucidated. In fact, the incomplete
molecular characterization of SGTs was identified by the NIH/NIDCR as a major roadblock to the creation of
new clinical diagnostics and therapies. Thus, a comprehensive understanding of the mechanisms driving
MEC development and progression is critical to developing better therapeutic interventions. The Aims
of this proposal address these significant knowledge gaps through the seamless integration of expertise, tools,
and technologies, assembled by our group to investigate how coordinated regulation of two key signaling
pathways by a CRTC1-MAML2 (C1/M2) fusion oncogene regulates differentiation and tumor grade in salivary
MEC. The C1/M2 fusion is recognized as a key defining feature occurring in over 50% of MEC cases, which
reprograms the CREB transcriptional network to drive tumorigenesis. However, in addition to CREB, our recent
work and exciting Preliminary Studies now reveal that the C1/M2 oncoprotein also harbors gain-of-function
properties that enable MYC binding and co-activation of the MYC transcriptional network. Mechanistically, our
data reveal an etiologic role for C1/M2 in the altered cell heterogeneity associated with advanced salivary MEC,
identify IGF-1 signaling as a hallmark of fusion positive MEC, and uncover antagonistic roles for C1/M2-CREB
versus C1/M2-MYC in promoting differentiation or de-differentiation, respectively. Moreover, we developed and
validated the first autochthonous mouse model of salivary MEC that faithfully mimics the genetic and
pathologic features of human disease. Therefore, our central hypothesis states that C1/M2 influences intra-
tumoral heterogeneity during salivary MEC development and progression by balancing expression of
CREB and MYC transcriptional programs that control cell differentiation. To interrogate the molecular
and cellular events that initiate, maintain the malignant state, and mediate response to therapy, we also
developed an innovative optical reporter and mouse model that permits longitudinal characterization of
tumorigenesis. In Specific Aim 1 we will establish whether IGF-1 regulation promotes MEC tumorigenesis and
drug resistance. In Specific Aim 2 we will elucidate the mechanisms governing C1/M2 interactions with MYC
and the functional significance of these interactions, and in Specific Aim 3 we will determine the clinical
significance of regulating CREB versus MYC in relation to MEC pathology.

Grant Number: 5R01DE030123-06
NIH Institute/Center: NIH
Principal Investigator: Antonio Amelio