Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 10, Pages 4390-4404Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI65856
Keywords
-
Categories
Funding
- NIH [CA89849, DE15953, DE20649, DE019712, CA149456, CA052607, T32 CA 174648]
- Radiological Society of North America Medical Student Research Grant
- University of Colorado School of Medicine Research Track
- University of Colorado Cancer Center FACS Core [P30 CA046934]
Ask authors/readers for more resources
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 a-catenin as a predominant miR-9 target. Increased miR-9 in human SCC metastases correlated with a-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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available