Identification of a human airway epithelial cell subpopulation with altered biophysical, molecular, and metastatic properties

Paul C. Pagano, Linh M. Tran, Nawal Bendris, Sean O'Byrne, Henry T. Tse, Shivani Sharma, Jonathan W. Hoech, Stacy J. Park, Elvira L. Liclican, Zhe Jing, Rui Li, Kostyantyn Krysan, Manash K. Paul, Yari Fontebasso, Jill E. Larsen, Shaina Hakimi, Atsuko Seki, Michael C. Fishbein, James K. Gimzewski, Dino Di Carlo & 3 others John D. Minna, Tonya C. Walser, Steven M. Dubinett

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)514-524
Number of pages11
JournalCancer Prevention Research
Volume10
Issue number9
DOIs
StatePublished - Sep 1 2017

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Forensic Anthropology
Epithelial Cells
Lung Neoplasms
Cell Line
Lung
Genetic Heterogeneity
Constriction
Cell Division
Cell Movement
Maintenance
Phenotype
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Identification of a human airway epithelial cell subpopulation with altered biophysical, molecular, and metastatic properties. / Pagano, Paul C.; Tran, Linh M.; Bendris, Nawal; O'Byrne, Sean; Tse, Henry T.; Sharma, Shivani; Hoech, Jonathan W.; Park, Stacy J.; Liclican, Elvira L.; Jing, Zhe; Li, Rui; Krysan, Kostyantyn; Paul, Manash K.; Fontebasso, Yari; Larsen, Jill E.; Hakimi, Shaina; Seki, Atsuko; Fishbein, Michael C.; Gimzewski, James K.; Di Carlo, Dino; Minna, John D.; Walser, Tonya C.; Dubinett, Steven M.

In: Cancer Prevention Research, Vol. 10, No. 9, 01.09.2017, p. 514-524.

Research output: Contribution to journalArticle

Pagano, PC, Tran, LM, Bendris, N, O'Byrne, S, Tse, HT, Sharma, S, Hoech, JW, Park, SJ, Liclican, EL, Jing, Z, Li, R, Krysan, K, Paul, MK, Fontebasso, Y, Larsen, JE, Hakimi, S, Seki, A, Fishbein, MC, Gimzewski, JK, Di Carlo, D, Minna, JD, Walser, TC & Dubinett, SM 2017, 'Identification of a human airway epithelial cell subpopulation with altered biophysical, molecular, and metastatic properties', Cancer Prevention Research, vol. 10, no. 9, pp. 514-524. https://doi.org/10.1158/1940-6207.CAPR-16-0335
Pagano, Paul C. ; Tran, Linh M. ; Bendris, Nawal ; O'Byrne, Sean ; Tse, Henry T. ; Sharma, Shivani ; Hoech, Jonathan W. ; Park, Stacy J. ; Liclican, Elvira L. ; Jing, Zhe ; Li, Rui ; Krysan, Kostyantyn ; Paul, Manash K. ; Fontebasso, Yari ; Larsen, Jill E. ; Hakimi, Shaina ; Seki, Atsuko ; Fishbein, Michael C. ; Gimzewski, James K. ; Di Carlo, Dino ; Minna, John D. ; Walser, Tonya C. ; Dubinett, Steven M. / Identification of a human airway epithelial cell subpopulation with altered biophysical, molecular, and metastatic properties. In: Cancer Prevention Research. 2017 ; Vol. 10, No. 9. pp. 514-524.
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T1 - Identification of a human airway epithelial cell subpopulation with altered biophysical, molecular, and metastatic properties

AU - Pagano, Paul C.

AU - Tran, Linh M.

AU - Bendris, Nawal

AU - O'Byrne, Sean

AU - Tse, Henry T.

AU - Sharma, Shivani

AU - Hoech, Jonathan W.

AU - Park, Stacy J.

AU - Liclican, Elvira L.

AU - Jing, Zhe

AU - Li, Rui

AU - Krysan, Kostyantyn

AU - Paul, Manash K.

AU - Fontebasso, Yari

AU - Larsen, Jill E.

AU - Hakimi, Shaina

AU - Seki, Atsuko

AU - Fishbein, Michael C.

AU - Gimzewski, James K.

AU - Di Carlo, Dino

AU - Minna, John D.

AU - Walser, Tonya C.

AU - Dubinett, Steven M.

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N2 - 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.

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