Shi-Long Lu, MD, PhD
Departments of Otolaryngology, Dermatology, Pathology
University of Colorado Anschutz Medical Campus
Research Complex 2, Room 7112 (office), 7460 (lab)
12700 E 19th Avenue
Aurora, CO 80045
Tel: (303)-724-3074 (office), (303)-724-5340 (lab)
The prognosis of head and neck squamous cell carcinoma (HNSCC) patients remains poor, with a 5-year survival rate of less than 50%. The poor prognosis of this disease is primarily due to tumor invasion to adjacent organs, local-regional recurrence, and distant metastasis. Treatment intervening tumor invasion, recurrence and metastasis, are thus crucial for controlling HNSCC progression. However, the molecular and cellular processes of HNSCC progression are poorly understood.
Our laboratory applies a multidisciplinary approach to analyze the molecular basis of HNSCC invasion, recurrence, and metastasis, combining modern molecular biology and genomics tools with animal models and advanced in vivo imaging technologies. We welcome application for graduate, postdoctoral, and undergraduate research, as well as resident and medical student research rotation in our laboratory in the following subjects:
1. 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.
2. Molecular identification and characterization of metastatic cancer stem cells and their niche.
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. 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 metastatic cancer stem cells. Currently, our laboratory is trying to identify and characterize the metastatic cancer stem cells and their niche, which will not only help us for better understanding of the biology of HNSCC recurrence and metastasis, but also develop better therapeutical strategies.
3. 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.
Current Lab members:
Xi Chen (Graduate Student, CANB program)
Masako Oka (Postdoctoral Associate)
Li Du (Postdoctoral Associate)
Jingping Shen (PRA)
Fang Zhang (Lab Manager)
1. Lu SL, Reh D, Li AG, Woods J, Corless CL, Kulesz-Martin M, Wang XJ: Overexpression of transforming growth factor beta1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation. Cancer Res. 64: 4405-4410 (2004).
2. Li AG, Lu SL, Zhang MX, Deng C, Wang XJ: Smad3 knockout mice exhibit a resistance to skin chemical carcinogenesis. Cancer Res. 64: 7836-7845 (2004).
3. Han G, Lu SL, LiAG, He W, Corless CL, Kulesz-Martin M, Wang XJ: Distinct mechanisms of TGFbeta1-mediated epithelial-mesenchymal transition and metastasis during skin carcinogenesis. J Clin Invest. 115: 1714-1723 (2005).
4. Lu SL, Herrington H, Reh D, Weber S, Bernstein S, Wang D, Tang CF, Siddiqui Y, Nord J, Andersen P, Corless C, Wang XJ: Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev. 20: 1331-1342 (2006).
5. Koster MI, Lu SL, White LD, Wang XJ, Roop DR: Reactivation of developmentally expressed p63 isoforms predispose to tumor development and progression. Cancer Res. 66: 3981-3986 (2006).
6. Lu SL, Herrington H, Wang XJ: Mouse models for human head and neck squamous cell carcinomas. Head & Neck 28: 945-54 (2006).
7. Bornstein S, White R, Malkoski S, Reh D, Anderson P, Gross N, Olson S, Deng CX, Lu SL*, Wang XJ: Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest. 119: 3408-3419 (2009) [Editorial by Murray Korc "Smad4: gatekeeper gene in head and neck squamous cell carcinoma". J Clin Invest. 119: 3208-3212 (2009)] *=Co-corresponding author.
8. Weber S, Bornstein S, Li, Y, Malkoski S, Wang D, Rustgi A, Kulesz-Martin M, Wang XJ, Lu SL: Tobacco-specific carcinogen nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone induces AKT activation in head and neck epithelia. Int. J Oncol. 39:1193-1198 (2011)
9. Minor J, Wang X, Zhang F, Song J, Jimeno A, Wang XJ, Lu X, Gross N, Kulesz-Martin M, Wang D, Lu SL: Methylation of microRNA-9 is a specific and sensitive biomarker for oral and oropharyngeal squamous cell carcinomas. Oral Oncol. 48: 73-8 (2012)
10. Du L, Shen J, Weems A, Lu SL: Role of phosphatidylinositol-3-kinase pathway in head and neck squamous cell carcinoma. J Oncol. 450179 (2012)