TGF-β signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts

Guangcun Huang; Pawel A. Osmulski; Hakim Bouamar; Devalingam Mahalingam; Chun Lin Lin; Michael A. Liss; Addanki Pratap Kumar; Chun Liang Chen; Ian M. Thompson; Lu Zhe Sun; Maria E. Gaczynska; Tim H M Huang

doi:10.18632/oncotarget.12808

TGF-β signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts

Guangcun Huang, Pawel A. Osmulski, Hakim Bouamar, Devalingam Mahalingam, Chun Lin Lin, Michael A. Liss, Addanki Pratap Kumar, Chun Liang Chen, Ian M. Thompson, Lu Zhe Sun, Maria E. Gaczynska, Tim H M Huang

Medicine, Hematology Oncology Division

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

12 Scopus citations

Abstract

Activation of TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) for the development of metastatic castration-resistant prostate cancer (mCRPC). To determine whether targeting TGF-β signaling alone is sufficient to mitigate mCRPC, we used the CRISPR/Cas9 genome-editing approach to generate a dominant-negative mutation of the cognate receptor TGFBRII that attenuated TGF-β signaling in mCRPC cells. As a result, the delicate balance of oncogenic homeostasis is perturbed, profoundly uncoupling proliferative and metastatic potential of TGFBRII-edited tumor xenografts. This signaling disturbance triggered feedback rewiring by enhancing ERK signaling known to promote EMT-driven metastasis. Circulating tumor cells displaying upregulated EMT genes had elevated biophysical deformity and an increase in interactions with chaperone macrophages for facilitating metastatic extravasation. Treatment with an ERK inhibitor resulted in decreased aggressive features of CRPC cells in vitro. Therefore, combined targeting of TGF-β and its backup partner ERK represents an attractive strategy for treating mCRPC patients.

Original language	English (US)
Pages (from-to)	77124-77137
Number of pages	14
Journal	Oncotarget
Volume	7
Issue number	47
DOIs	https://doi.org/10.18632/oncotarget.12808
State	Published - 2016

Funding

The authors wish to thank the staff of the Bioanlaytics and Single-Cell Core at the University of Texas Health Science Center-San Antonio for providing their technique support of single-cell expression analysis This work was supported by NIH grants R01CA172886, U54CA113001, and P30CA054174; the Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150600; gift of the Cancer Therapy and Research Center Foundation; and the Max and Minnie Tomerlin Voelcker Fund

Keywords

Circulating tumor cells
Epithelial-mesenchymal transition (EMT)
Positive feedback signaling
Transforming growth factor-β (TGF-β)
Tumor metastasis

ASJC Scopus subject areas

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/oncotarget.12808

Cite this

Huang, G., Osmulski, P. A., Bouamar, H., Mahalingam, D., Lin, C. L., Liss, M. A., Kumar, A. P., Chen, C. L., Thompson, I. M., Sun, L. Z., Gaczynska, M. E., & Huang, T. H. M. (2016). TGF-β signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts. Oncotarget, 7(47), 77124-77137. https://doi.org/10.18632/oncotarget.12808

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title = "TGF-β signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts",

abstract = "Activation of TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) for the development of metastatic castration-resistant prostate cancer (mCRPC). To determine whether targeting TGF-β signaling alone is sufficient to mitigate mCRPC, we used the CRISPR/Cas9 genome-editing approach to generate a dominant-negative mutation of the cognate receptor TGFBRII that attenuated TGF-β signaling in mCRPC cells. As a result, the delicate balance of oncogenic homeostasis is perturbed, profoundly uncoupling proliferative and metastatic potential of TGFBRII-edited tumor xenografts. This signaling disturbance triggered feedback rewiring by enhancing ERK signaling known to promote EMT-driven metastasis. Circulating tumor cells displaying upregulated EMT genes had elevated biophysical deformity and an increase in interactions with chaperone macrophages for facilitating metastatic extravasation. Treatment with an ERK inhibitor resulted in decreased aggressive features of CRPC cells in vitro. Therefore, combined targeting of TGF-β and its backup partner ERK represents an attractive strategy for treating mCRPC patients.",

keywords = "Circulating tumor cells, Epithelial-mesenchymal transition (EMT), Positive feedback signaling, Transforming growth factor-β (TGF-β), Tumor metastasis",

author = "Guangcun Huang and Osmulski, {Pawel A.} and Hakim Bouamar and Devalingam Mahalingam and Lin, {Chun Lin} and Liss, {Michael A.} and Kumar, {Addanki Pratap} and Chen, {Chun Liang} and Thompson, {Ian M.} and Sun, {Lu Zhe} and Gaczynska, {Maria E.} and Huang, {Tim H M}",

note = "Funding Information: The authors wish to thank the staff of the Bioanlaytics and Single-Cell Core at the University of Texas Health Science Center-San Antonio for providing their technique support of single-cell expression analysis This work was supported by NIH grants R01CA172886, U54CA113001, and P30CA054174; the Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150600; gift of the Cancer Therapy and Research Center Foundation; and the Max and Minnie Tomerlin Voelcker Fund",

year = "2016",

doi = "10.18632/oncotarget.12808",

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volume = "7",

pages = "77124--77137",

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T1 - TGF-β signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts

AU - Huang, Guangcun

AU - Osmulski, Pawel A.

AU - Bouamar, Hakim

AU - Mahalingam, Devalingam

AU - Lin, Chun Lin

AU - Liss, Michael A.

AU - Kumar, Addanki Pratap

AU - Chen, Chun Liang

AU - Thompson, Ian M.

AU - Sun, Lu Zhe

AU - Gaczynska, Maria E.

AU - Huang, Tim H M

N1 - Funding Information: The authors wish to thank the staff of the Bioanlaytics and Single-Cell Core at the University of Texas Health Science Center-San Antonio for providing their technique support of single-cell expression analysis This work was supported by NIH grants R01CA172886, U54CA113001, and P30CA054174; the Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150600; gift of the Cancer Therapy and Research Center Foundation; and the Max and Minnie Tomerlin Voelcker Fund

PY - 2016

Y1 - 2016

N2 - Activation of TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) for the development of metastatic castration-resistant prostate cancer (mCRPC). To determine whether targeting TGF-β signaling alone is sufficient to mitigate mCRPC, we used the CRISPR/Cas9 genome-editing approach to generate a dominant-negative mutation of the cognate receptor TGFBRII that attenuated TGF-β signaling in mCRPC cells. As a result, the delicate balance of oncogenic homeostasis is perturbed, profoundly uncoupling proliferative and metastatic potential of TGFBRII-edited tumor xenografts. This signaling disturbance triggered feedback rewiring by enhancing ERK signaling known to promote EMT-driven metastasis. Circulating tumor cells displaying upregulated EMT genes had elevated biophysical deformity and an increase in interactions with chaperone macrophages for facilitating metastatic extravasation. Treatment with an ERK inhibitor resulted in decreased aggressive features of CRPC cells in vitro. Therefore, combined targeting of TGF-β and its backup partner ERK represents an attractive strategy for treating mCRPC patients.

AB - Activation of TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) for the development of metastatic castration-resistant prostate cancer (mCRPC). To determine whether targeting TGF-β signaling alone is sufficient to mitigate mCRPC, we used the CRISPR/Cas9 genome-editing approach to generate a dominant-negative mutation of the cognate receptor TGFBRII that attenuated TGF-β signaling in mCRPC cells. As a result, the delicate balance of oncogenic homeostasis is perturbed, profoundly uncoupling proliferative and metastatic potential of TGFBRII-edited tumor xenografts. This signaling disturbance triggered feedback rewiring by enhancing ERK signaling known to promote EMT-driven metastasis. Circulating tumor cells displaying upregulated EMT genes had elevated biophysical deformity and an increase in interactions with chaperone macrophages for facilitating metastatic extravasation. Treatment with an ERK inhibitor resulted in decreased aggressive features of CRPC cells in vitro. Therefore, combined targeting of TGF-β and its backup partner ERK represents an attractive strategy for treating mCRPC patients.

KW - Circulating tumor cells

KW - Epithelial-mesenchymal transition (EMT)

KW - Positive feedback signaling

KW - Transforming growth factor-β (TGF-β)

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ER -

TGF-β signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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