Epithelial stem cell mutations that promote squamous cell carcinoma metastasis.

White RA, Neiman JM, Reddi A, Han G, Birlea S, Mitra D, Dionne L, Fernandez P, Murao K, Bian L, Keysar SB, Goldstein NB, Song N, Bornstein S, Han Z, Lu X, Wisell J, Li F, Song J, Lu SL, Jimeno A, Roop DR, Wang XJ
J Clin Invest. 2013 123 (10): 4390-404

PMID: 23999427 · PMCID: PMC3784525 · DOI:10.1172/JCI65856

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.

MeSH Terms (26)

alpha Catenin Animals Carcinogenesis Carcinoma, Squamous Cell Cell Dedifferentiation Cell Proliferation Epithelial-Mesenchymal Transition Female Gene Expression Regulation, Neoplastic Humans Mice Mice, Nude Mice, Transgenic MicroRNAs Mutation, Missense Neoplasm Transplantation Neoplastic Stem Cells Proto-Oncogene Proteins Proto-Oncogene Proteins p21(ras) ras Proteins RNA Interference Sequence Deletion Side-Population Cells Skin Neoplasms Smad4 Protein Tumor Cells, Cultured

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