title: Epithelial stem cell mutations that promote squamous cell carcinoma metastasis.
abstract: Squamous cell carcinomas (SCCs) originate in stratified epithelia, with a small subset becoming metastatic. Epithelial stem cells are targets for driver mutations that give rise to SCCs, but it is unknown whether they contribute to oncogenic multipotency and metastasis. We developed a mouse model of SCC by targeting two frequent genetic mutations in human SCCs, oncogene Kras(G12D) activation and Smad4 deletion, to mouse keratin 15-expressing (K15+) stem cells. We show that transgenic mice developed multilineage tumors, including metastatic SCCs. Among cancer stem cell-enriched (CSC-enriched) populations, those with increased side population (SP) cells correlated with epithelial-mesenchymal transition (EMT) and lung metastasis. We show that microRNA-9 (miR-9) contributed to SP expansion and metastasis, and miR-9 inhibition reduced the number of SP cells and metastasis. Increased miR-9 was detected in metastatic human primary SCCs and SCC metastases, and miR-9-transduced human SCC cells exhibited increased invasion. We identified α-catenin as a predominant miR-9 target. Increased miR-9 in human SCC metastases correlated with α-catenin loss but not E-cadherin loss. Our results demonstrate that stem cells with Kras(G12D) activation and Smad4 depletion can produce tumors that are multipotent and susceptible to EMT and metastasis. Additionally, tumor initiation and metastatic properties of CSCs can be uncoupled, with miR-9 regulating the expansion of metastatic CSCs.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: White
authors.forename: Jill M
authors.initials: JM
authors.lastname: Neiman
authors.forename: Anand
authors.initials: A
authors.lastname: Reddi
authors.forename: Gangwen
authors.initials: G
authors.lastname: Han
authors.forename: Stanca
authors.initials: S
authors.lastname: Birlea
authors.forename: Doyel
authors.initials: D
authors.lastname: Mitra
authors.forename: Laikuan
authors.initials: L
authors.lastname: Dionne
authors.forename: Pam
authors.initials: P
authors.lastname: Fernandez
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Murao
authors.forename: Li
authors.initials: L
authors.lastname: Bian
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Keysar
authors.forename: Nathaniel B
authors.initials: NB
authors.lastname: Goldstein
authors.forename: Ningjing
authors.initials: N
authors.lastname: Song
authors.forename: Sophia
authors.initials: S
authors.lastname: Bornstein
authors.forename: Zheyi
authors.initials: Z
authors.lastname: Han
authors.forename: Xian
authors.initials: X
authors.lastname: Lu
authors.forename: Joshua
authors.initials: J
authors.lastname: Wisell
authors.forename: Fulun
authors.initials: F
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Song
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Lu
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Roop
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000556:secondary*; D054337:Cell Dedifferentiation; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D017384:Sequence Deletion; D058985:Side-Population Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D051901:Smad4 Protein / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051178:alpha Catenin / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D051178:alpha Catenin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins