TY - JOUR
T1 - Regulation of head and neck squamous cancer stem cells by PI3K and SOX2
AU - Keysar, Stephen B.
AU - Le, Phuong N.
AU - Miller, Bettina
AU - Jackson, Brian C.
AU - Eagles, Justin R.
AU - Nieto, Cera
AU - Kim, Jihye
AU - Tang, Binwu
AU - Glogowska, Magdalena J.
AU - Morton, J. Jason
AU - Padilla-Just, Nuria
AU - Gomez, Karina
AU - Warnock, Emily
AU - Reisinger, Julie
AU - Arcaroli, John J.
AU - Messersmith, Wells A.
AU - Wakefield, Lalage M.
AU - Gao, Dexiang
AU - Tan, Aik Choon
AU - Serracino, Hilary
AU - Vasiliou, Vasilis
AU - Roop, Dennis R.
AU - Wang, Xiao Jing
AU - Jimeno, Antonio
N1 - Publisher Copyright:
© The Author 2016. Published by Oxford University Press. All rights reserved.
PY - 2017/1
Y1 - 2017/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85014859275&partnerID=8YFLogxK
U2 - 10.1093/jnci/djw189
DO - 10.1093/jnci/djw189
M3 - Article
C2 - 27634934
AN - SCOPUS:85014859275
SN - 0027-8874
VL - 109
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 1
ER -
