Oncotarget

Priority Research Papers:

Llgl1 prevents metaplastic survival driven by epidermal growth factor dependent migration

Erin Greenwood, Sabrina Maisel, David Ebertz, Atlantis Russ, Ritu Pandey and Joyce Schroeder _

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Oncotarget. 2016; 7:60776-60792. https://doi.org/10.18632/oncotarget.11320

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Abstract

Erin Greenwood1, Sabrina Maisel2,5,*, David Ebertz1,*, Atlantis Russ1,4, Ritu Pandey2,6 and Joyce Schroeder1,2,3,4,5

1 Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona

2 Arizona Cancer Center, University of Arizona, Tucson, Arizona

3 BIO5 Institute, University of Arizona, Tucson, Arizona

4 Genetics Program, University of Arizona, Tucson, Arizona

5 Cancer Biology Program, University of Arizona, Tucson, Arizona

6 Cell and Molecular Medicine, University of Arizona, Tucson, Arizona

* These two authors have contributed equally to this work

Correspondence to:

Joyce Schroeder, email:

Keywords: polarity, migration, Llgl1, epidermal growth factor receptor, TAZ

Received: July 20, 2016 Accepted: August 02, 2016 Published: August 17, 2016

Abstract

We 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-SCIDmice. 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.


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