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Regulation and role of actin dynamics in promoting premalignant cell migration. / K. Paul, Manash; Basu, Arkaprabha; Bisht, Bharti; Pagano, Paul; Fontebasso, Yari; Krysan, Kostyantyn; Tran, Linh; Alioscha-Perez, Mitchel; Minna, John; DiCarlo, Dino; Sahli, Hichem; Weiss, Shimon; M. Dubinett, Steven.

CANCER RESEARCH. Vol. 79 13. ed. 2019. p. 1030-1030.

Research output: Chapter in Book/Report/Conference proceedingConference paperResearch

Harvard

K. Paul, M, Basu, A, Bisht, B, Pagano, P, Fontebasso, Y, Krysan, K, Tran, L, Alioscha-Perez, M, Minna, J, DiCarlo, D, Sahli, H, Weiss, S & M. Dubinett, S 2019, Regulation and role of actin dynamics in promoting premalignant cell migration. in CANCER RESEARCH. 13 edn, vol. 79, pp. 1030-1030, AACR 2019 Anual Meeting, Atlanta, United States, 29/03/19. https://doi.org/10.1158/1538-7445.SABCS18-1030

APA

K. Paul, M., Basu, A., Bisht, B., Pagano, P., Fontebasso, Y., Krysan, K., ... M. Dubinett, S. (2019). Regulation and role of actin dynamics in promoting premalignant cell migration. In CANCER RESEARCH (13 ed., Vol. 79, pp. 1030-1030) https://doi.org/10.1158/1538-7445.SABCS18-1030

Vancouver

K. Paul M, Basu A, Bisht B, Pagano P, Fontebasso Y, Krysan K et al. Regulation and role of actin dynamics in promoting premalignant cell migration. In CANCER RESEARCH. 13 ed. Vol. 79. 2019. p. 1030-1030 https://doi.org/10.1158/1538-7445.SABCS18-1030

Author

K. Paul, Manash ; Basu, Arkaprabha ; Bisht, Bharti ; Pagano, Paul ; Fontebasso, Yari ; Krysan, Kostyantyn ; Tran, Linh ; Alioscha-Perez, Mitchel ; Minna, John ; DiCarlo, Dino ; Sahli, Hichem ; Weiss, Shimon ; M. Dubinett, Steven. / Regulation and role of actin dynamics in promoting premalignant cell migration. CANCER RESEARCH. Vol. 79 13. ed. 2019. pp. 1030-1030

BibTeX

@inproceedings{7f0bea0f9a7e4c71bea21e5c003c2980,
title = "Regulation and role of actin dynamics in promoting premalignant cell migration",
abstract = "Lung cancer is a highly metastatic disease. Although commonly considered to be a late event in disease pathogenesis, micrometastasis may also occur as an early phenomenon. Induction of epithelial-mesenchymal transition (EMT) is associated with changes in mechanical properties, predominantly due to increased cell contractility and actin stress fiber formation. The molecular mechanisms regulating actin dynamics during EMT in premalignant cells have not yet been defined. Using a novel constricted migration selection strategy and physomic techniques, including deformability cytometry and atomic force microscopy, we identified a highly motile (HM) subpopulation of HBECs, with enhanced heritable migratory capacity both in vitro and in vivo. The HBECs used for selection were modified with genetic changes that can be found in premalignancy (p53null, activated Kras-G12D). Thus, this sub-population of HM-HBECs offer a unique model to investigate premalignant cell migration. Comparative RNA-seq datasets and confocal live cell imaging technology reveal increased migration and expression of key EMT genes in HM-HBECs. HM-HBECs cells were found to be characterized by the transient accumulation of actin stress fibers as compared to parental-HBECs. We performed high-throughput kinase inhibitor screening to better understand the role of kinases regulating early HBEC migration. Incucyte based secondary screen assays established that ERK-MEK pathway inhibition plays a key role in inhibiting actin stress fiber formation and actin-associated protein network assembly thereby delaying early migration. In the absence of a sensitive quantitative method to detect actin cytoskeleton remodeling in a non-destructive manner, we developed computational methods to extract and quantify the actin stress fibers from Super Resolution Optical Fluctuation imaging (SOFI) and confocal microscopic images. SOFI-based fluorescence imaging based on temporal, stochastic “on” and “off” fluorescence fluctuations in combination with actin-tagged blinking fluorescent proteins such as Dronpa showed advantages over methods that use fixed samples in studying actin filament assembly and disassembly. We extracted the orientations of the fibers and the width of their distribution in each time point to quantitatively distinguish different architectures. Our preliminary data suggest a Rac1-Cortactin-actin dynamic regulatory axis that may lead to enhanced migration. This is accompanied by orientation of actin fibers favoring EMT. Future studies are anticipated to identify novel targets in premalignancy that could be exploited for lung cancer interception.",
keywords = "Actin cytoskeleton, Super Resolution Optical Fluctuation imaging, Epithelial-mesenchymal transition (EMT), Micrometastases",
author = "{K. Paul}, Manash and Arkaprabha Basu and Bharti Bisht and Paul Pagano and Yari Fontebasso and Kostyantyn Krysan and Linh Tran and Mitchel Alioscha-Perez and John Minna and Dino DiCarlo and Hichem Sahli and Shimon Weiss and {M. Dubinett}, Steven",
year = "2019",
month = "7",
doi = "10.1158/1538-7445.SABCS18-1030",
language = "English",
volume = "79",
pages = "1030--1030",
booktitle = "CANCER RESEARCH",
edition = "13",

}

RIS

TY - GEN

T1 - Regulation and role of actin dynamics in promoting premalignant cell migration

AU - K. Paul, Manash

AU - Basu, Arkaprabha

AU - Bisht, Bharti

AU - Pagano, Paul

AU - Fontebasso, Yari

AU - Krysan, Kostyantyn

AU - Tran, Linh

AU - Alioscha-Perez, Mitchel

AU - Minna, John

AU - DiCarlo, Dino

AU - Sahli, Hichem

AU - Weiss, Shimon

AU - M. Dubinett, Steven

PY - 2019/7

Y1 - 2019/7

N2 - Lung cancer is a highly metastatic disease. Although commonly considered to be a late event in disease pathogenesis, micrometastasis may also occur as an early phenomenon. Induction of epithelial-mesenchymal transition (EMT) is associated with changes in mechanical properties, predominantly due to increased cell contractility and actin stress fiber formation. The molecular mechanisms regulating actin dynamics during EMT in premalignant cells have not yet been defined. Using a novel constricted migration selection strategy and physomic techniques, including deformability cytometry and atomic force microscopy, we identified a highly motile (HM) subpopulation of HBECs, with enhanced heritable migratory capacity both in vitro and in vivo. The HBECs used for selection were modified with genetic changes that can be found in premalignancy (p53null, activated Kras-G12D). Thus, this sub-population of HM-HBECs offer a unique model to investigate premalignant cell migration. Comparative RNA-seq datasets and confocal live cell imaging technology reveal increased migration and expression of key EMT genes in HM-HBECs. HM-HBECs cells were found to be characterized by the transient accumulation of actin stress fibers as compared to parental-HBECs. We performed high-throughput kinase inhibitor screening to better understand the role of kinases regulating early HBEC migration. Incucyte based secondary screen assays established that ERK-MEK pathway inhibition plays a key role in inhibiting actin stress fiber formation and actin-associated protein network assembly thereby delaying early migration. In the absence of a sensitive quantitative method to detect actin cytoskeleton remodeling in a non-destructive manner, we developed computational methods to extract and quantify the actin stress fibers from Super Resolution Optical Fluctuation imaging (SOFI) and confocal microscopic images. SOFI-based fluorescence imaging based on temporal, stochastic “on” and “off” fluorescence fluctuations in combination with actin-tagged blinking fluorescent proteins such as Dronpa showed advantages over methods that use fixed samples in studying actin filament assembly and disassembly. We extracted the orientations of the fibers and the width of their distribution in each time point to quantitatively distinguish different architectures. Our preliminary data suggest a Rac1-Cortactin-actin dynamic regulatory axis that may lead to enhanced migration. This is accompanied by orientation of actin fibers favoring EMT. Future studies are anticipated to identify novel targets in premalignancy that could be exploited for lung cancer interception.

AB - Lung cancer is a highly metastatic disease. Although commonly considered to be a late event in disease pathogenesis, micrometastasis may also occur as an early phenomenon. Induction of epithelial-mesenchymal transition (EMT) is associated with changes in mechanical properties, predominantly due to increased cell contractility and actin stress fiber formation. The molecular mechanisms regulating actin dynamics during EMT in premalignant cells have not yet been defined. Using a novel constricted migration selection strategy and physomic techniques, including deformability cytometry and atomic force microscopy, we identified a highly motile (HM) subpopulation of HBECs, with enhanced heritable migratory capacity both in vitro and in vivo. The HBECs used for selection were modified with genetic changes that can be found in premalignancy (p53null, activated Kras-G12D). Thus, this sub-population of HM-HBECs offer a unique model to investigate premalignant cell migration. Comparative RNA-seq datasets and confocal live cell imaging technology reveal increased migration and expression of key EMT genes in HM-HBECs. HM-HBECs cells were found to be characterized by the transient accumulation of actin stress fibers as compared to parental-HBECs. We performed high-throughput kinase inhibitor screening to better understand the role of kinases regulating early HBEC migration. Incucyte based secondary screen assays established that ERK-MEK pathway inhibition plays a key role in inhibiting actin stress fiber formation and actin-associated protein network assembly thereby delaying early migration. In the absence of a sensitive quantitative method to detect actin cytoskeleton remodeling in a non-destructive manner, we developed computational methods to extract and quantify the actin stress fibers from Super Resolution Optical Fluctuation imaging (SOFI) and confocal microscopic images. SOFI-based fluorescence imaging based on temporal, stochastic “on” and “off” fluorescence fluctuations in combination with actin-tagged blinking fluorescent proteins such as Dronpa showed advantages over methods that use fixed samples in studying actin filament assembly and disassembly. We extracted the orientations of the fibers and the width of their distribution in each time point to quantitatively distinguish different architectures. Our preliminary data suggest a Rac1-Cortactin-actin dynamic regulatory axis that may lead to enhanced migration. This is accompanied by orientation of actin fibers favoring EMT. Future studies are anticipated to identify novel targets in premalignancy that could be exploited for lung cancer interception.

KW - Actin cytoskeleton

KW - Super Resolution Optical Fluctuation imaging

KW - Epithelial-mesenchymal transition (EMT)

KW - Micrometastases

U2 - 10.1158/1538-7445.SABCS18-1030

DO - 10.1158/1538-7445.SABCS18-1030

M3 - Conference paper

VL - 79

SP - 1030

EP - 1030

BT - CANCER RESEARCH

ER -

ID: 40318287