Epithelial stem cell mutations that promote Squamous cell carcinoma metastasis

Ruth A. White, Jill M. Neiman, Anand Reddi, Gangwen Han, Stanca Birlea, Doyel Mitra, Laikuan Dionne, Pam Fernandez, Kazutoshi Murao, Li Bian, Stephen B. Keysar, Nathaniel B. Goldstein, Ningjing Song, Sophia Bornstein, Zheyi Han, Xian Lu, Joshua Wisell, Fulun Li, John Song, Shi Long LuAntonio Jimeno, Dennis R. Roop, Xiao Jing Wang

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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 KrasG12D 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.

Original languageEnglish (US)
Pages (from-to)4390-4404
Number of pages15
JournalJournal of Clinical Investigation
Volume123
Issue number10
DOIs
StatePublished - Oct 1 2013

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Squamous Cell Carcinoma
Stem Cells
Epithelial Cells
Neoplasm Metastasis
Mutation
MicroRNAs
Side-Population Cells
Catenins
Epithelial-Mesenchymal Transition
Keratin-15
Neoplasms
Neoplastic Stem Cells
Cadherins
Oncogenes
Transgenic Mice
Population
Epithelium
Lung

ASJC Scopus subject areas

  • Medicine(all)

Cite this

White, R. A., Neiman, J. M., Reddi, A., Han, G., Birlea, S., Mitra, D., ... Wang, X. J. (2013). Epithelial stem cell mutations that promote Squamous cell carcinoma metastasis. Journal of Clinical Investigation, 123(10), 4390-4404. https://doi.org/10.1172/JCI65856

Epithelial stem cell mutations that promote Squamous cell carcinoma metastasis. / White, Ruth A.; Neiman, Jill M.; Reddi, Anand; Han, Gangwen; Birlea, Stanca; Mitra, Doyel; Dionne, Laikuan; Fernandez, Pam; Murao, Kazutoshi; Bian, Li; Keysar, Stephen B.; Goldstein, Nathaniel B.; Song, Ningjing; Bornstein, Sophia; Han, Zheyi; Lu, Xian; Wisell, Joshua; Li, Fulun; Song, John; Lu, Shi Long; Jimeno, Antonio; Roop, Dennis R.; Wang, Xiao Jing.

In: Journal of Clinical Investigation, Vol. 123, No. 10, 01.10.2013, p. 4390-4404.

Research output: Contribution to journalArticle

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 2013, 'Epithelial stem cell mutations that promote Squamous cell carcinoma metastasis', Journal of Clinical Investigation, vol. 123, no. 10, pp. 4390-4404. https://doi.org/10.1172/JCI65856
White RA, Neiman JM, Reddi A, Han G, Birlea S, Mitra D et al. Epithelial stem cell mutations that promote Squamous cell carcinoma metastasis. Journal of Clinical Investigation. 2013 Oct 1;123(10):4390-4404. https://doi.org/10.1172/JCI65856
White, Ruth A. ; Neiman, Jill M. ; Reddi, Anand ; Han, Gangwen ; Birlea, Stanca ; Mitra, Doyel ; Dionne, Laikuan ; Fernandez, Pam ; Murao, Kazutoshi ; Bian, Li ; Keysar, Stephen B. ; Goldstein, Nathaniel B. ; Song, Ningjing ; Bornstein, Sophia ; Han, Zheyi ; Lu, Xian ; Wisell, Joshua ; Li, Fulun ; Song, John ; Lu, Shi Long ; Jimeno, Antonio ; Roop, Dennis R. ; Wang, Xiao Jing. / Epithelial stem cell mutations that promote Squamous cell carcinoma metastasis. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 10. pp. 4390-4404.
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AU - Neiman, Jill M.

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AU - Mitra, Doyel

AU - Dionne, Laikuan

AU - Fernandez, Pam

AU - Murao, Kazutoshi

AU - Bian, Li

AU - Keysar, Stephen B.

AU - Goldstein, Nathaniel B.

AU - Song, Ningjing

AU - Bornstein, Sophia

AU - Han, Zheyi

AU - Lu, Xian

AU - Wisell, Joshua

AU - Li, Fulun

AU - Song, John

AU - Lu, Shi Long

AU - Jimeno, Antonio

AU - Roop, Dennis R.

AU - Wang, Xiao Jing

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N2 - 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 KrasG12D 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.

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