TY - JOUR
T1 - Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating properties
AU - Bragado, Paloma
AU - Estrada, Yeriel
AU - Sosa, Maria Soledad
AU - Avivar-Valderas, Alvaro
AU - Cannan, David
AU - Genden, Eric
AU - Teng, Marita
AU - Ranganathan, Aparna C.
AU - Wen, Huei Chi
AU - Kapoor, Avnish
AU - Bernstein, Emily
AU - Aguirre-Ghiso, Julio A.
PY - 2012/1/20
Y1 - 2012/1/20
N2 - Head and neck squamous carcinoma (HNSCC) tumors carry dismal long-term prognosis and the role of tumor initiating cells (TICs) in this cancer is unclear. We investigated in HNSCC xenografts whether specific tumor subpopulations contributed to tumor growth. We used a CFSE-based label retentions assay, CD49f (α6-integrin) surface levels and aldehyde dehydrogenase (ALDH) activity to profile HNSCC subpopulations. The tumorigenic potential of marker-positive and -negative subpopulations was tested in nude (Balb/c nu/nu) and NSG (NOD.Cg-Prkdc scid Il2rg tm1Wjl/SzJ) mice and chicken embryo chorioallantoic membrane (CAM) assays. Here we identified in HEp3, SQ20b and FaDu HNSCC xenografts a subpopulation of G0/G1-arrested slow-cycling CD49f high/ALDH1A1 high/H3K4/K27me3 low subpopulation (CD49f+) of tumor cells. A strikingly similar CD49f high/H3K27me3 low subpopulation is also present in primary human HNSCC tumors and metastases. While only sorted CD49f high/ALDH high, label retaining cells (LRC) proliferated immediately in vivo, with time the CD49f low/ALDH low, non-LRC (NLRC) tumor cell subpopulations were also able to regain tumorigenic capacity; this was linked to restoration of CD49f high/ALDH high, label retaining cells. In addition, CD49f is required for HEp3 cell tumorigenicity and to maintain low levels of H3K4/K27me3. CD49f+ cells also displayed reduced expression of the histone-lysine N-methyltransferase EZH2 and ERK1/2phosphorylation. This suggests that although transiently quiescent, their unique chromatin structure is poised for rapid transcriptional activation. CD49f- cells can "reprogram" and also achieve this state eventually. We propose that in HNSCC tumors, epigenetic mechanisms likely driven by CD49f signaling dynamically regulate HNSCC xenograft phenotypic heterogeneity. This allows multiple tumor cell subpopulations to drive tumor growth suggesting that their dynamic nature renders them a "moving target" and their eradication might require more persistent strategies.
AB - Head and neck squamous carcinoma (HNSCC) tumors carry dismal long-term prognosis and the role of tumor initiating cells (TICs) in this cancer is unclear. We investigated in HNSCC xenografts whether specific tumor subpopulations contributed to tumor growth. We used a CFSE-based label retentions assay, CD49f (α6-integrin) surface levels and aldehyde dehydrogenase (ALDH) activity to profile HNSCC subpopulations. The tumorigenic potential of marker-positive and -negative subpopulations was tested in nude (Balb/c nu/nu) and NSG (NOD.Cg-Prkdc scid Il2rg tm1Wjl/SzJ) mice and chicken embryo chorioallantoic membrane (CAM) assays. Here we identified in HEp3, SQ20b and FaDu HNSCC xenografts a subpopulation of G0/G1-arrested slow-cycling CD49f high/ALDH1A1 high/H3K4/K27me3 low subpopulation (CD49f+) of tumor cells. A strikingly similar CD49f high/H3K27me3 low subpopulation is also present in primary human HNSCC tumors and metastases. While only sorted CD49f high/ALDH high, label retaining cells (LRC) proliferated immediately in vivo, with time the CD49f low/ALDH low, non-LRC (NLRC) tumor cell subpopulations were also able to regain tumorigenic capacity; this was linked to restoration of CD49f high/ALDH high, label retaining cells. In addition, CD49f is required for HEp3 cell tumorigenicity and to maintain low levels of H3K4/K27me3. CD49f+ cells also displayed reduced expression of the histone-lysine N-methyltransferase EZH2 and ERK1/2phosphorylation. This suggests that although transiently quiescent, their unique chromatin structure is poised for rapid transcriptional activation. CD49f- cells can "reprogram" and also achieve this state eventually. We propose that in HNSCC tumors, epigenetic mechanisms likely driven by CD49f signaling dynamically regulate HNSCC xenograft phenotypic heterogeneity. This allows multiple tumor cell subpopulations to drive tumor growth suggesting that their dynamic nature renders them a "moving target" and their eradication might require more persistent strategies.
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U2 - 10.1371/journal.pone.0029974
DO - 10.1371/journal.pone.0029974
M3 - Article
C2 - 22276135
AN - SCOPUS:84856044714
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 1
M1 - e29974
ER -
