Regulation of head and neck squamous cancer stem cells by PI3K and SOX2

Stephen B. Keysar, Phuong N. Le, Bettina Miller, Brian C. Jackson, Justin R. Eagles, Cera Nieto, Jihye Kim, Binwu Tang, Magdalena J. Glogowska, J. Jason Morton, Nuria Padilla-Just, Karina Gomez, Emily Warnock, Julie Reisinger, John J. Arcaroli, Wells A. Messersmith, Lalage M. Wakefield, Dexiang Gao, Aik-Choon Tan, Hilary SerracinoVasilis Vasiliou, Dennis R. Roop, Xiao Jing Wang, Antonio Jimeno

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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). Sorted 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 1x103 cells: ALDHpCD44high = 65.8%, ALDH-CD44high = 33.1%, ALDHpCD44high = 20.0%; and injecting 1x105 cells: ALDH-CD44low = 4.4%). CSCs were resistant to conventional therapy and had PI3K/mTOR pathway overexpression (GSEA pathway enrichment, P < .001), and PI3K inhibition in vivo decreased their tumorigenicity (40.0%-100.0% across cases). PI3K/mTOR directly regulated SOX2 protein levels, and SOX2 in turn activated ALDH1A1 (P < .001 013C and 067C) expression and ALDH activity (ALDHp [%] empty-control vs SOX2, 0.4% 6 0.4% vs 14.5% 6 9.8%, P = .03 for 013C and 1.7% 6 1.3% vs 3.6% 6 3.4%, P = .04 for 067C) in 013C and 067 cells. SOX2 enhanced sphere and tumor growth (spheres/well, 013C P < .001 and 067C P = .04) and therapy resistance. SOX2 expression prompted mesenchymal-to-epithelial transition (MET) by inducing CDH1 (013C P = .002, 067C P = .01), followed by asymmetric division and proliferation, which contributed to tumor formation.

Original languageEnglish
Article numberdjw189
JournalJournal of the National Cancer Institute
Volume109
Issue number1
DOIs
Publication statusPublished - 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Keysar, S. B., Le, P. N., Miller, B., Jackson, B. C., Eagles, J. R., Nieto, C., Kim, J., Tang, B., Glogowska, M. J., Morton, J. J., Padilla-Just, N., Gomez, K., Warnock, E., Reisinger, J., Arcaroli, J. J., Messersmith, W. A., Wakefield, L. M., Gao, D., Tan, A-C., ... Jimeno, A. (2017). Regulation of head and neck squamous cancer stem cells by PI3K and SOX2. Journal of the National Cancer Institute, 109(1), [djw189]. https://doi.org/10.1093/jnci/djw189