Llgl1 prevents metaplastic survival driven by epidermal growth factor dependent migration
AffiliationUniv Arizona, Dept Mol & Cellular Biol
Univ Arizona, Arizona Canc Ctr
Univ Arizona, Inst BIO5
Univ Arizona, Genet Program
Univ Arizona, Canc Biol Program
Univ Arizona, Cell & Mol Med
MetadataShow full item record
PublisherIMPACT JOURNALS LLC
CitationGreenwood, Erin, et al. "Llgl1 prevents metaplastic survival driven by epidermal growth factor dependent migration." Oncotarget 7.38 (2016): 60776-60792.
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AbstractWe have previously demonstrated that Llgl1 loss results in a gain of mesenchymal phenotypes and a loss of apicobasal and planar polarity. We now demonstrate that these changes represent a fundamental shift in cellular phenotype. Llgl1 regulates the expression of multiple cell identity markers, including CD44, CD49f, and CD24, and the nuclear translocation of TAZ and Slug. Cells lacking Llgl1 form mammospheres, where survival and transplantability is dependent upon the Epidermal Growth Factor Receptor (EGFR). Additionally, Llgl1 loss allows cells to grow in soft-agar and maintain prolonged survival as orthotopic transplants in NOD-SCID mice. Lineage tracing and wound healing experiments demonstrate that mammosphere survival is due to enhanced EGF-dependent migration. The loss of Llgl1 drives EGFR mislocalization and an EGFR mislocalization point mutation (P667A) drives these same phenotypes, including activation of AKT and TAZ nuclear translocation. Together, these data indicate that the loss of Llgl1 results in EGFR mislocalization, promoting pre-neoplastic changes.
VersionFinal published version
SponsorsNIH [NIH CA023074, T32CA009213, NIGMS T32 GM008659]; NCI [CCSG P30 CA023074]