Role of PI3K/PTEN/AKT pathway in HNSCC progression.
The phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT pathway regulates cell growth, survival, motility, and metabolism. In vitro studies indicate that deregulation of this pathway is important in HNSCC tumorigenesis, as has been observed in several other cancers. However, the in vivo role of PI3K/PTEN/AKT pathway deregulation in HNSCC remains unknown. Using our head and neck specific genetically engineered mouse model (GEMM), this laboratory developed inducible head and neck specific transgenic PIK3CA and AKT mice, and inducible head and neck specific knockout PTEN mice.
Studies on each molecule revealed both the linear connection of PI3K/PTEN/AKT in the canonical pathway, as well as non-overlapping functions of each molecule transduced through distinct signaling. Dissecting this critical yet complicated signaling pathway is undergoing in this laboratory by cross-species comparison between the unique mouse models developed in this laboratory and human HNSCC clinical tissues.
These studies will reveal the roles of PIK3CA, PTEN, and AKT during each stage and site involving in head and neck tumorigenesis, and identify novel molecular markers for HNSCC prognosis and therapeutics.
Molecular characterization of migrating cancer progenitor cells
The cancer stem cells hypothesis has been extensively tested in many types of solid tumors including HNSCC. However, the role of these cells in HNSCC progression, particularly in metastasis has not been well defined.
Given the heterogynous population in tumors, it is reasonable to speculate there is a distinct population of cancer cells responsible for tumor metastasis (termed here as migrating cancer progenitor cells). PI3K pathway has been shown to maintain stem-like cell population in multiple cancers.
One unique feature of the HNSCC tumors from our PI3K GEMM models is epithelial-mesenchymal transition, which may generate multiple, distinct cellular population contributing to intratumoral heterogeneity and enrich the population of tentative migrating cancer progenitor cells.
Currently, our laboratory is trying to identify and characterize this unique cell subpopulation, which will not only help us for better understanding of the biology of HNSCC recurrence and metastasis, but also develop better therapeutical strategies.
Development of biomarkers from fine needle aspirates (FNA) for surveillance of HNSCC patients.
Lymph node metastasis is the single most important clinical prognostic factor in HNSCC. In addition, it is the most reliable predictor of treatment outcomes for HNSCC patients, and determines the strategies of clinical management for HNSCC patients.
Therefore, accurate assessment of the metastatic lymph nodes of HNSCC patients is of paramount importance. FNA biopsy of lymph node metastases is an excellent resource for this purpose. FNA possesses the advantages of easy accessibility, and minimal invasiveness, which is ideal for monitoring HNSCC patients during their disease process. However, the sensitivity of traditional cytology methods of FNA is less than satisfactory.
Additionally, cytology alone can rarely provide prognostic information, as well as guidance for therapeutic decisions. Thus, taking advantage of our unique HNSCC GEMMs, this laboratory is currently developing novel biomarkers with high sensitivity and specificity by cross-species comparison using state-of-art cancer genetics/epigenetics technologies. The goal is to develop biomarkers from FNA as surrogates to predict prognosis of HNSCC patients and to make therapeutic decision.