Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation

Sang Hyun Lee; Jin Man Kim; Dong Gwang Lee; Jangwook Lee; Jong Gil Park; Tae Su Han; Hyun Soo Cho; Young Lai Cho; Kwang Hee Bae; Young Jun Park; Seon Jin Lee; Moo Seung Lee; Yong Min Huh; Deog Yeon Jo; Hwan Jung Yun; Heung Jin Jeon; Nayoung Kim; Mina Joo; Jang Seong Kim; Hyo Jin Lee; Jeong Ki Min

doi:10.1038/s41418-020-00628-4

Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation

Sang Hyun Lee, Jin Man Kim, Dong Gwang Lee, Jangwook Lee, Jong Gil Park, Tae Su Han, Hyun Soo Cho, Young Lai Cho, Kwang Hee Bae, Young Jun Park, Seon Jin Lee, Moo Seung Lee, Yong Min Huh, Deog Yeon Jo, Hwan Jung Yun, Heung Jin Jeon, Nayoung Kim, Mina Joo, Jang Seong Kim, Hyo Jin LeeJeong Ki Min

Department of Radiology

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.

Original language	English
Pages (from-to)	968-984
Number of pages	17
Journal	Cell Death and Differentiation
Volume	28
Issue number	3
DOIs	https://doi.org/10.1038/s41418-020-00628-4
Publication status	Published - 2021 Mar

Bibliographical note

Funding Information:
Acknowledgements This study was supported by a grant from the Korea Research Institute of Bioscience and Biotechnology and by grants from the National Research Foundation of Korea, which was funded by the Ministry of Science, Information & Communication Technology and Future Planning (NRF-2015M3A9D7029882, NRF-2013M3A9B6046566, NRF-2018R1A2B2006724, NRF-2017R1D1A 1B04034638, and NRF-2017R1A5A2015385)

Publisher Copyright:
© 2020, The Author(s).

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1038/s41418-020-00628-4

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Lee, S. H., Kim, J. M., Lee, D. G., Lee, J., Park, J. G., Han, T. S., Cho, H. S., Cho, Y. L., Bae, K. H., Park, Y. J., Lee, S. J., Lee, M. S., Huh, Y. M., Jo, D. Y., Yun, H. J., Jeon, H. J., Kim, N., Joo, M., Kim, J. S., ... Min, J. K. (2021). Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation. Cell Death and Differentiation, 28(3), 968-984. https://doi.org/10.1038/s41418-020-00628-4

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title = "Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation",

abstract = "Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.",

author = "Lee, {Sang Hyun} and Kim, {Jin Man} and Lee, {Dong Gwang} and Jangwook Lee and Park, {Jong Gil} and Han, {Tae Su} and Cho, {Hyun Soo} and Cho, {Young Lai} and Bae, {Kwang Hee} and Park, {Young Jun} and Lee, {Seon Jin} and Lee, {Moo Seung} and Huh, {Yong Min} and Jo, {Deog Yeon} and Yun, {Hwan Jung} and Jeon, {Heung Jin} and Nayoung Kim and Mina Joo and Kim, {Jang Seong} and Lee, {Hyo Jin} and Min, {Jeong Ki}",

note = "Funding Information: Acknowledgements This study was supported by a grant from the Korea Research Institute of Bioscience and Biotechnology and by grants from the National Research Foundation of Korea, which was funded by the Ministry of Science, Information & Communication Technology and Future Planning (NRF-2015M3A9D7029882, NRF-2013M3A9B6046566, NRF-2018R1A2B2006724, NRF-2017R1D1A 1B04034638, and NRF-2017R1A5A2015385) Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2021",

month = mar,

doi = "10.1038/s41418-020-00628-4",

language = "English",

volume = "28",

pages = "968--984",

journal = "Cell Death and Differentiation",

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Lee, SH, Kim, JM, Lee, DG, Lee, J, Park, JG, Han, TS, Cho, HS, Cho, YL, Bae, KH, Park, YJ, Lee, SJ, Lee, MS, Huh, YM, Jo, DY, Yun, HJ, Jeon, HJ, Kim, N, Joo, M, Kim, JS, Lee, HJ & Min, JK 2021, 'Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation', Cell Death and Differentiation, vol. 28, no. 3, pp. 968-984. https://doi.org/10.1038/s41418-020-00628-4

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T1 - Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation

AU - Lee, Sang Hyun

AU - Kim, Jin Man

AU - Lee, Dong Gwang

AU - Lee, Jangwook

AU - Park, Jong Gil

AU - Han, Tae Su

AU - Cho, Hyun Soo

AU - Cho, Young Lai

AU - Bae, Kwang Hee

AU - Park, Young Jun

AU - Lee, Seon Jin

AU - Lee, Moo Seung

AU - Huh, Yong Min

AU - Jo, Deog Yeon

AU - Yun, Hwan Jung

AU - Jeon, Heung Jin

AU - Kim, Nayoung

AU - Joo, Mina

AU - Kim, Jang Seong

AU - Lee, Hyo Jin

AU - Min, Jeong Ki

N1 - Funding Information: Acknowledgements This study was supported by a grant from the Korea Research Institute of Bioscience and Biotechnology and by grants from the National Research Foundation of Korea, which was funded by the Ministry of Science, Information & Communication Technology and Future Planning (NRF-2015M3A9D7029882, NRF-2013M3A9B6046566, NRF-2018R1A2B2006724, NRF-2017R1D1A 1B04034638, and NRF-2017R1A5A2015385) Publisher Copyright: © 2020, The Author(s).

PY - 2021/3

Y1 - 2021/3

N2 - Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.

AB - Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.

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Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation

Abstract

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