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.
Highlights
Squamous cell carcinomas (SCCs) are derived from stratified epithelia present within the skin and oral cavity
We found that UV-induced SCCs did not exhibit morphological changes similar to those in the transplanted K15.KrasG12D.Smad4–/– SCCs, nor did they develop lung metastasis, suggesting that the increase in epithelial-mesenchymal transition (EMT) and metastasis in passaged tumors is unique to tumors that develop from K15.KrasG12D.Smad4–/– cells
The deletion of Smad4 or PTEN in stratified epithelial cells resulted in the formation of multilineage tumors (SCCs, basal cell carcinoma (BCC), trichoepitheliomas, and sebaceous adenomas) corresponding to all major skin stem cell lineages [5, 32, 54]
Summary
Squamous cell carcinomas (SCCs) are derived from stratified epithelia present within the skin and oral cavity. Very few genetic mutations causing spontaneous SCC formation and metastasis have been found, metastasis to the lung, which is the leading cause of SCC-associated death [3]. Mice with a Smad deletion in stratified epithelia develop spontaneous SCCs in the skin, oral cavity, and forestomach [4,5,6]. Among these models, oral SCCs metastasize to lymph nodes [4], whereas skin and forestomach SCCs do not metastasize [5, 6]
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