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  Targeting mechanoresponsive proteins in pancreatic cancer: 4-hydroxyacetophenone blocks dissemitation and invation by activating MYH14

Surcel, A., Schiffhauer, E. S., Thomas, D. G., Zhu, Q., DiNapoli, K. T., Herbig, M., et al. (2019). Targeting mechanoresponsive proteins in pancreatic cancer: 4-hydroxyacetophenone blocks dissemitation and invation by activating MYH14. Cancer research: an official organ of the American Association for Cancer Research, 79(18), 4665-4678. doi:10.1158/0008-5472.CAN-18-3131.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0006-07C8-1 Version Permalink: https://hdl.handle.net/21.11116/0000-0006-0F90-7
Genre: Journal Article

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 Creators:
Surcel, Alexandra1, Author
Schiffhauer, Eric S1, Author
Thomas, Dustin G1, Author
Zhu, Quingfeng1, Author
DiNapoli, Kathleen T1, Author
Herbig, Maik2, Author
Otto, Oliver2, Author
West-Foyle, Hoku1, Author
Jacobi, Angela2, Author
Kräter, Martin2, Author
Plak, Katarzyna2, Author
Guck, Jochen2, Author
Jaffee, Elizabeth M1, Author
Iglesias, Pablo A1, Author
Anders, Robert A1, Author
Robinson, Douglas N1, Author
Affiliations:
1External Organizations, ou_persistent22              
2Biotechnology Center, Technische Universität Dresden, Germany, ou_persistent22              

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 Abstract: Metastasis is complex, involving multiple genetic, epigenetic, biochemical, and physical changes in the cancer cell and its microenvironment. Cells with metastatic potential are often characterized by altered cellular contractility and deformability, lending them the flexibility to disseminate and navigate through different microenvironments. We demonstrate that mechanoresponsiveness is a hallmark of pancreatic cancer cells. Key mechanoresponsive proteins, those that accumulate in response to mechanical stress, specifically nonmuscle myosin IIA (MYH9) and IIC (MYH14), α-actinin 4, and filamin B, were highly expressed in pancreatic cancer as compared with healthy ductal epithelia. Their less responsive sister paralogs—myosin IIB (MYH10), α-actinin 1, and filamin A—had lower expression differential or disappeared with cancer progression. We demonstrate that proteins whose cellular contributions are often overlooked because of their low abundance can have profound impact on cell architecture, behavior, and mechanics. Here, the low abundant protein MYH14 promoted metastatic behavior and could be exploited with 4-hydroxyacetophenone (4-HAP), which increased MYH14 assembly, stiffening cells. As a result, 4-HAP decreased dissemination, induced cortical actin belts in spheroids, and slowed retrograde actin flow. 4-HAP also reduced liver metastases in human pancreatic cancer-bearing nude mice. Thus, increasing MYH14 assembly overwhelms the ability of cells to polarize and invade, suggesting targeting the mechanoresponsive proteins of the actin cytoskeleton as a new strategy to improve the survival of patients with pancreatic cancer.

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Language(s): eng - English
 Dates: 2018-10-042019-07-222019-07-292019-09-15
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1158/0008-5472.CAN-18-3131
PII: canres.3131.2018.
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Title: Cancer research : an official organ of the American Association for Cancer Research
  Other : Cancer Res.
Source Genre: Journal
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Publ. Info: Baltimore, Md. : Waverly Press
Pages: 13 Volume / Issue: 79 (18) Sequence Number: - Start / End Page: 4665 - 4678 Identifier: ISSN: 0008-5472
CoNE: https://pure.mpg.de/cone/journals/resource/991042743115962