title: Targeting BMI1+Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma.
abstract: Squamous cell carcinoma in the head and neck (HNSCC) is a common yet poorly understood cancer, with adverse clinical outcomes due to treatment resistance, recurrence, and metastasis. Putative cancer stem cells (CSCs) have been identified in HNSCC, and BMI1 expression has been linked to these phenotypes, but optimal treatment strategies to overcome chemotherapeutic resistance and eliminate metastases have not yet been identified. Here we show through lineage tracing and genetic ablation that BMI1+CSCs mediate invasive growth and cervical lymph node metastasis in a mouse model of HNSCC. This model and primary human HNSCC samples contain highly tumorigenic, invasive, and cisplatin-resistant BMI1+CSCs, which exhibit increased AP-1 activity that drives invasive growth and metastasis of HNSCC. Inhibiting AP-1 or BMI1 sensitized tumors to cisplatin-based chemotherapy, and it eliminated lymph node metastases by targeting CSCs and the tumor bulk, suggesting potential regimens to overcome resistance to treatments and eradicate HNSCC metastasis.
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Demeng
authors.initials: D
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Mansi
authors.initials: M
authors.lastname: Wu
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Insoon
authors.initials: I
authors.lastname: Chang
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Ekimyan-Salvo
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Deng
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Dong
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Szymanski
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Ramadoss
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA; Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA 90095, USA. Electronic address: cwang@dentistry.ucla.edu.
authors.forename: Cun-Yu
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; C489421:Bmi1 protein, mouse; D011518:Proto-Oncogene Proteins; D063150:Polycomb Repressive Complex 1; D002945:Cisplatin
keywords: AP-1; Bmi1; cancer stem cells; chemotherapy; cisplatin resistance; head and neck squamous cell carcinoma; metastasis