Regulation of Head and Neck Squamous Cancer Stem Cells by PI3K and SOX2

Abstract

Background: We have an incomplete understanding of the differences between cancer stem cells (CSCs) in human papillomavirus-positive (HPV-positive) and -negative (HPV-negative) head and neck squamous cell cancer (HNSCC). The PI3K pathway has the most frequent activating genetic events in HNSCC (especially HPV-positive driven), but the differential signaling between CSCs and non-CSCs is also unknown. Methods: We addressed these unresolved questions using CSCs identified from 10 HNSCC patient-derived xenografts (PDXs). Sored populations were serially passaged in nude mice to evaluate tumorigenicity and tumor recapitulation. The transcription profile of HNSCC CSCs was characterized by mRNA sequencing, and the susceptibility of CSCs to therapy was investigated using an in vivo model. SOX2 transcriptional activity was used to follow the asymmetric division of PDX-derived CSCs. All statistical tests were two-sided. Results: CSCs were enriched by high aldehyde dehydrogenase (ALDH) activity and CD44 expression and were similar between HPV-positive and HPV-negative cases (percent tumor formation injecting 1x10 3 cells: ALDH þ CD44 high ¼ 65.8%,

Wnt signaling dynamics in head and neck squamous cell cancer tumor‐stroma interactions

“…We then assessed protein expression in 013C cells that actively invaded versus those that did not (cell scraping of membrane) when either media or 013CAF cells were used as chemoattractant. Regardless of chemoattractant, non‐invading cells expressed significantly higher levels of Sox2 by densitometry (Figure C and Supplementary Table S2), similar to previous results showing HNSCC CSCs to be highly epithelial . Non‐invading 013C cells exposed to both Wnt3a and CAFs as chemoattractant had dramatically upregulated Twist1, while Twist1 was decreased in invading cells under these conditions (Figures B and C and Supplementary Table S2).…”

“…Having shown the effects of forced Wnt expression/signaling and the interplay between tumor and TME in vitro, we next inhibited endogenous Wnt signaling in highly tumorigenic HNSCC CSCs, such as in CUHN014 tumors, where as few as 10 ALDH + CD44 high cells readily generate tumors . Mice bearing CUHN014 tumors, as well as mice that would be the recipient of CSC implantations, were treated for 2 weeks with vehicle or OMP‐54F28 and continued treating CSC recipient mice 2 weeks following implantation.…”

Epigenetic down‐regulation of SOX2 is an independent poor prognostic factor for hypopharyngeal cancers

“…The mechanisms by which SOX2 participates in tumorigenesis remain elusive. In a study using cancer stem cells isolated from head and neck squamous cell carcinomas, SOX2 expression enhanced sphere formation, tumour growth, therapy resistance, and mesenchymal epithelial transition . These proto‐oncogenic roles are expected to be relevant in SOX2 ‐amplified cancers.…”

Molecular mechanisms of human papillomavirus-related carcinogenesis in head and neck cancer

“…Additionally, it plays a role in the reprogramming of somatic cells, reversing their epigenetic configuration back to the pluripotent embryonic state [60]. Evidence of amplification of this gene provides a mechanism for conversion of squamous cells to cancer stem cells, a concept that has been supported by other studies [61]. …”