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(+)CD44(high) = 65.8%, ALDH(-)CD44(high) = 33.1%, ALDH(+)CD44(high) = 20.0%; and injecting 1x10(5) cells: ALDH(-)CD44(low) = 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 (ALDH(+) [%] empty-control vs SOX2, 0.4% ± 0.4% vs 14.5% ± 9.8%, P = .03 for 013C and 1.7% ± 1.3% vs 3.6% ± 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. Conclusions: The molecular link between PI3K activation and CSC properties found in this study provides insights into therapeutic strategies for HNSCC. Constitutive expression of SOX2 in HNSCC cells generates a CSC-like population that enables CSC studies.
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(+)CD44(high) = 65.8%, ALDH(-)CD44(high) = 33.1%, ALDH(+)CD44(high) = 20.0%; and injecting 1x10(5) cells: ALDH(-)CD44(low) = 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 (ALDH(+) [%] empty-control vs SOX2, 0.4% ± 0.4% vs 14.5% ± 9.8%, P = .03 for 013C and 1.7% ± 1.3% vs 3.6% ± 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. Conclusions: The molecular link between PI3K activation and CSC properties found in this study provides insights into therapeutic strategies for HNSCC. Constitutive expression of SOX2 in HNSCC cells generates a CSC-like population that enables CSC studies.
Authors: Michael F Clarke; John E Dick; Peter B Dirks; Connie J Eaves; Catriona H M Jamieson; D Leanne Jones; Jane Visvader; Irving L Weissman; Geoffrey M Wahl Journal: Cancer Res Date: 2006-09-21 Impact factor: 12.701
Authors: Ahmedin Jemal; Taylor Murray; Elizabeth Ward; Alicia Samuels; Ram C Tiwari; Asma Ghafoor; Eric J Feuer; Michael J Thun Journal: CA Cancer J Clin Date: 2005 Jan-Feb Impact factor: 508.702
Authors: Vivian W Y Lui; Matthew L Hedberg; Hua Li; Bhavana S Vangara; Kelsey Pendleton; Yan Zeng; Yiling Lu; Qiuhong Zhang; Yu Du; Breean R Gilbert; Maria Freilino; Sam Sauerwein; Noah D Peyser; Dong Xiao; Brenda Diergaarde; Lin Wang; Simion Chiosea; Raja Seethala; Jonas T Johnson; Seungwon Kim; Umamaheswar Duvvuri; Robert L Ferris; Marjorie Romkes; Tomoko Nukui; Patrick Kwok-Shing Ng; Levi A Garraway; Peter S Hammerman; Gordon B Mills; Jennifer R Grandis Journal: Cancer Discov Date: 2013-04-25 Impact factor: 39.397
Authors: Binwu Tang; Asaf Raviv; Dominic Esposito; Kathleen C Flanders; Catherine Daniel; Bao Tram Nghiem; Susan Garfield; Langston Lim; Poonam Mannan; Ana I Robles; William I Smith; Joshua Zimmerberg; Rea Ravin; Lalage M Wakefield Journal: Stem Cell Reports Date: 2014-12-11 Impact factor: 7.765
Authors: Kari R Fischer; Anna Durrans; Sharrell Lee; Jianting Sheng; Fuhai Li; Stephen T C Wong; Hyejin Choi; Tina El Rayes; Seongho Ryu; Juliane Troeger; Robert F Schwabe; Linda T Vahdat; Nasser K Altorki; Vivek Mittal; Dingcheng Gao Journal: Nature Date: 2015-11-11 Impact factor: 49.962
Authors: Glaucia Maria de Mendonça Fernandes; Ana Lívia Silva Galbiatti-Dias; Leticia Antunes Muniz Ferreira; Vilson Serafim Junior; Gabriela Helena Rodrigues-Fleming; Juliana Garcia de Oliveira-Cucolo; Patrícia Matos Biselli-Chicote; Rosa Sayoko Kawasaki-Oyama; José Victor Maniglia; Érika Cristina Pavarino; Eny Maria Goloni-Bertollo Journal: Am J Transl Res Date: 2021-01-15 Impact factor: 4.060
Authors: Stephen B Keysar; Justin R Eagles; Bettina Miller; Brian C Jackson; Farshad N Chowdhury; Julie Reisinger; Tugs-Saikhan Chimed; Phuong N Le; John J Morton; Hilary L Somerset; Marileila Varella-Garcia; Aik-Choon Tan; John I Song; Daniel W Bowles; Mary E Reyland; Antonio Jimeno Journal: Clin Cancer Res Date: 2018-03-19 Impact factor: 12.531
Authors: Farshad N Chowdhury; Julie Reisinger; Karina E Gomez; Tugs-Saikhan Chimed; Carissa M Thomas; Phuong N Le; Bettina Miller; John J Morton; Cera M Nieto; Hilary L Somerset; Xiao-Jing Wang; Stephen B Keysar; Antonio Jimeno Journal: Oral Oncol Date: 2019-10-03 Impact factor: 5.337
Authors: Karina E Gomez; FangLong Wu; Stephen B Keysar; J Jason Morton; Bettina Miller; Tugs-Saikhan Chimed; Phuong N Le; Cera Nieto; Farshad N Chowdhury; Anit Tyagi; Traci R Lyons; Christian D Young; Hongmei Zhou; Hilary L Somerset; Xiao-Jing Wang; Antonio Jimeno Journal: Cancer Res Date: 2020-08-14 Impact factor: 12.701