American Head & Neck Society
Translational Research Meeting

April 21-22, 2015

AHNS Annual Meeting
April 22-23, 2015 during the
Combined Otolaryngology Spring Meetings

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Cd271 Modulates The Invasive And Metastatic Phenotype Of Head And Neck Squamous Cell Carcinoma Tumor-initiating Cells Through The Upregulation Of Slug

Presentation: S019
Topic: Stem Cells in Cancer
Type: TRM
Date: Wednesday, April 22, 2015
Session: 11:15 am - 12:15 pm
Authors: Manki Chung, MD1, Young Ho Jung, MD2, Joon Kyoo Lee, MD3, Oihana Murillo-Sauca4, Ravindra Uppaluri, MD5, June Ho Shin, PhD4, John B Sunwoo, MD4
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Institution(s): 1Department of Otorhinolaryngology - Head & Neck Surgery, Sungkyunkwan University School of Medicine, 2Department of Otolaryngology-Head & Neck Surgery, Seoul National University College of Medicine, 3Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Medical School, 4Division of Head and Neck Surgery, Department of Otolaryngology; Stanford Cancer Institute, 5Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine
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Head and neck squamous cell carcinoma (HNSCC) is comprised of heterogeneous populations of cells. Discrete subpopulations with distinct marker phenotypes and functional characteristics have been defined. Recently, we have identified CD271 (low-affinity nerve growth factor receptor; p75NTR) as a functional marker of a tumor-initiating cell subpopulation in HNSCC1. CD271+ cells, which comprise a subset of the CD44+ cells, signals through the MAPK pathway and promote tumor formation. In the current study, we used a murine model of HNSCC (MOC2 cell line derived from DMBA-treated oral cavities of mice) that has been previously characterized and described2. As with human HNSCC, the MOC2 cells also have a subpopulation of cells that express CD271.

When MOC2 cells were transduced to express NGFR by lentivirus (MOC2-NGFR), a more robust metastatic phenotype was observed. Specifically, when MOC2-NGFR cells were implanted orthotopically into the oral cavities of C57BL/6 mouse, there was a significantly higher rate of regional lymph node metastasis in mice implanted with the MOC2-NGFR cells compared to the parental MOC2 cells (91.6%, 11/12 in MOC2-NGFR cells vs. 30.0%, 3/10 in mice implanted with parental MOC2 cells). Furthermore, MOC2-NGFR cells were significantly more invasive in an invasion chamber assay, and this enhanced invasive phenotype could be abrogated by a blocking anti-CD271 antibody.

To understand the molecular basis, mRNA expression profiles of epithelial-to-mesenchymal (EMT) transition-related genes were assessed in the MOC2-NGFR and MOC2 parental cells. We observed a significantly greater expression of Snai2 mRNA (which codes for the transcription factor Slug) in the CD271-NGFR cells. Notably, the activation of CD271 by recombinant NGF resulted in higher Snai2 mRNA expression, measured by RT-qPCR, and Slug protein, measured by Western blot analysis. In addition, incubation with NGF enhanced the invasive phenotype in vitro to a significantly greater extent in the MOC2-NGFR cells compared to the parental MOC2, and this effect of NGF was abrogated when Snai2 was knocked down by shRNA, indicating that the invasive phenotype conferred by CD271 activation was dependent on Snai2 expression.

Finally, we show that these findings are relevant to human HNSCC. Specifically, Snai2 mRNA expression was observed to be higher in CD271+CD44+ subpopulation compared to the CD271-CD44+ subpopulation, sorted from patient derived xenografts. In addition, when CD271 expression was measured quantitatively by immunohistochemical analysis of human oral SCC tumors (all initially staged clinically as T3-4N0M0), tumors, associated with pathologically discovered nodal metastases, had higher CD271 expression compared to tumors from patients without nodal metastasis.

Thus, our data indicate that activation of the tumor-initiating cell marker CD271 results in upregulation of Snai2/Slug, which, in turn, results in a more invasive phenotype and the enhanced capacity for metastasis to regional lymph nodes. These findings point to CD271 as a promising target for therapy.


1.         Murillo-Sauca, O., et al. CD271 is a functional and targetable marker of tumor-initiating cells in head and neck squamous cell carcinoma. Oncotarget 5, 6854-6866 (2014).

2.         Judd, N.P., et al. ERK1/2 Regulation of CD44 Modulates Oral Cancer Aggressiveness. Cancer Res 72, 365-374 (2012).

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