Adenoid cystic carcinoma (ACC) remains a poorly characterized cancer with no reliable molecular markers and useful therapeutic targets. Among head and neck tumors, ACC is distinguished by slow but relentless course, remarkable propensity to invade and grow along nerves, and late recurrences both locally and distantly. Treatment options are limited to surgery with or without radiation, and if surgery is not possible, there is no therapy for recurrence. We recently found that the majority of ACCs (17 of 18, or ~94%) express high levels of the neurotrophin receptor tyrosine kinase TrkC, whereas mucoepidermoid (MEC) and head and neck squamous cell carcinomas (HNSCC) are TrkC-negative. TrkC functions as a dependence receptor meaning that its signaling can result in either survival or apoptosis depending on availability of its only known ligand NT- 3. The pro-survival axis requires NT-3-induced TrkC autophosphorylation. In cancers, however, pro-survival TrkC signaling may either bypass the requirement for its ligand via activating mutations/fusions or rely on autocrine NT-3 production. To validate our hypothesis that activated TrkC promotes ACC growth, cell migration, and invasion, we put forward three specific aims. First, to determine if TrkC signaling in ACC can be activated via mutations, fusions, or abnormal splicing, we will determine if TrkC splicoforms, mutations, or gene fusions occur in ACC. Our initial study on a small-size ACC cohort (n=6) revealed an alternative del8 splicoform that lacks 8 aa in the region adjacent to the ligand-binding domain. Working on an expanded cohort of ACC patients, we will continue the quest for TrkC aberrations that may affect TrkC signaling. Our next aim is to define the roles for NT-3 with canonical and del8 TrkC splice variants in pro-tumorigenic activities. We demonstrated recently that clinical ACC specimens express NT-3 suggesting autocrine TrkC activation and a pivotal role for NT-3 in ACC progression. In this aim, we will further explore the possibility of autocrine TrkC activation and analyze molecular and cellular consequences of NT-3-stimulated TrkC activation. Critical signaling events downstream of NT-3-activated canonical and del8 TrkC will be first explored in surrogate cell lines and validated in cultured ACC cells, clinical ACC specimens via IHC staining, and in our ACC mouse model.
Our third aim will explore TrkC/NT-3 roles in ACC growth and pro-survival signaling in a mouse model. Here, we will use Aim 2 data for in vivo validation and pre-clinical assessment of TrkC signaling inhibitors. Specifically, our preliminary data suggested that NT-3-stimulated TrkC activates the Ras- Erk 1/2 pathway with involvement of B-Raf, Mek 1/2, and Bcl2.
In Aim 3, we will assess NT-3 effects on ACC growth in vivo and use small-molecule inhibitors to block TrkC activation and downstream signaling as a pilot experiment for pre-clinical studies. The only available model of ACC, subcutaneous mouse xenografts, has been established in our preliminary work as an appropriate tool to study TrkC signaling. Overall, our data support exploration of TrkC signaling in ACC with the goal to develop an effective therapy against this cancer.
Adenoid cystic carcinoma (ACC), devastating and common salivary cancer, is notorious for nerve invasion and frequent late recurrence;however, treatment options are limited to surgery with or without radiation, and if surgery is not possible, there is o therapy for recurrence. Our discovery of markedly high TrkC expression and activation in ACC that bring about pro-survival and pro-invasive effects suggests that TrkC signaling is a driver of ACC growth and invasion mediated via NT-3-stimulated Ras-Erk 1/2 and Akt activation. A better understanding of the role of TrkC/NT-3 activity and downstream signaling in ACC is necessary to determine potential therapeutic utility of small-molecule inhibitors that block activation of TrC and its targets.
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| Panaccione, Alex; Zhang, Yi; Ryan, Molly et al. (2017) MYB fusions and CD markers as tools for authentication and purification of cancer stem cells from salivary adenoid cystic carcinoma. Stem Cell Res 21:160-166 |
| Panaccione, Alex; Guo, Yan; Yarbrough, Wendell G et al. (2017) Expression Profiling of Clinical Specimens Supports the Existence of Neural Progenitor-Like Stem Cells in Basal Breast Cancers. Clin Breast Cancer 17:298-306.e7 |
| Panaccione, Alex; Chang, Michael T; Carbone, Beatrice E et al. (2016) NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma. Clin Cancer Res 22:2083-95 |
