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Cancer Prev Res (Phila). 2017 Sep;10(9):514-524. doi: 10.1158/1940-6207.CAPR-16-0335. Epub 2017 Jul 28.

Identification of a Human Airway Epithelial Cell Subpopulation with Altered Biophysical, Molecular, and Metastatic Properties.

Author information

1
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.
2
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
3
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
4
Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas.
5
Department of Bioengineering, UCLA, Los Angeles, California.
6
Department of Chemistry and Biochemistry, UCLA, Los Angeles, California.
7
California NanoSystems Institute, Los Angeles, California.
8
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
9
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
10
Jonsson Comprehensive Cancer Center, Los Angeles, California.
11
Hamon Center for Therapeutic Oncology Research and Departments of Medicine and Pharmacology, UT Southwestern Medical Center, Dallas, Texas.
12
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California. sdubinett@mednet.ucla.edu.
13
VA Greater Los Angeles Health Care System, Los Angeles, California.

Abstract

Lung cancers are documented to have remarkable intratumoral genetic heterogeneity. However, little is known about the heterogeneity of biophysical properties, such as cell motility, and its relationship to early disease pathogenesis and micrometastatic dissemination. In this study, we identified and selected a subpopulation of highly migratory premalignant airway epithelial cells that were observed to migrate through microscale constrictions at up to 100-fold the rate of the unselected immortalized epithelial cell lines. This enhanced migratory capacity was found to be Rac1-dependent and heritable, as evidenced by maintenance of the phenotype through multiple cell divisions continuing more than 8 weeks after selection. The morphology of this lung epithelial subpopulation was characterized by increased cell protrusion intensity. In a murine model of micrometastatic seeding and pulmonary colonization, the motility-selected premalignant cells exhibit both enhanced survival in short-term assays and enhanced outgrowth of premalignant lesions in longer-term assays, thus overcoming important aspects of "metastatic inefficiency." Overall, our findings indicate that among immortalized premalignant airway epithelial cell lines, subpopulations with heritable motility-related biophysical properties exist, and these may explain micrometastatic seeding occurring early in the pathogenesis of lung cancer. Understanding, targeting, and preventing these critical biophysical traits and their underlying molecular mechanisms may provide a new approach to prevent metastatic behavior. Cancer Prev Res; 10(9); 514-24. ©2017 AACRSee related editorial by Hynds and Janes, p. 491.

PMID:
28754664
PMCID:
PMC5584580
DOI:
10.1158/1940-6207.CAPR-16-0335
[Indexed for MEDLINE]
Free PMC Article

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