Targeting mechanoresponsive proteins in pancreatic cancer

4-hydroxyacetophenone blocks dissemination and invasion by activating MYH14

Alexandra Surcel, Eric S. Schiffhauer, Dustin G. Thomas, Qingfeng Zhu, Kathleen T. DiNapoli, Maik Herbig, Oliver Otto, Hoku West-Foyle, Angela Jacobi, Martin Krater, Katarzyna Plak, Jochen Guck, Elizabeth Jaffee, Pablo A Iglesias, Robert A Anders, Douglas Robinson

Research output: Contribution to journalArticle

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), a-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), a-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-hydroxyaceto-phenone (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. Significance: This study demonstrates that mechanoresponsive proteins become upregulated with pancreatic cancer progression and that this system of proteins can be pharma-cologically targeted to inhibit the metastatic potential of pancreatic cancer cells.

Original languageEnglish (US)
Pages (from-to)4665-4678
Number of pages14
JournalCancer Research
Volume79
Issue number18
DOIs
StatePublished - Sep 15 2019

Fingerprint

Protein Transport
Pancreatic Neoplasms
Filamins
Actinin
Proteins
Actins
Nonmuscle Myosin Type IIA
Neoplasm Metastasis
Cellular Microenvironment
Mechanical Stress
Aptitude
Mechanics
Actin Cytoskeleton
Epigenomics
Nude Mice
4-hydroxyacetophenone
Siblings
Molecular Biology
Neoplasms
Epithelium

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting mechanoresponsive proteins in pancreatic cancer : 4-hydroxyacetophenone blocks dissemination and invasion by activating MYH14. / Surcel, Alexandra; Schiffhauer, Eric S.; Thomas, Dustin G.; Zhu, Qingfeng; DiNapoli, Kathleen T.; Herbig, Maik; Otto, Oliver; West-Foyle, Hoku; Jacobi, Angela; Krater, Martin; Plak, Katarzyna; Guck, Jochen; Jaffee, Elizabeth; Iglesias, Pablo A; Anders, Robert A; Robinson, Douglas.

In: Cancer Research, Vol. 79, No. 18, 15.09.2019, p. 4665-4678.

Research output: Contribution to journalArticle

Surcel, Alexandra ; Schiffhauer, Eric S. ; Thomas, Dustin G. ; Zhu, Qingfeng ; DiNapoli, Kathleen T. ; Herbig, Maik ; Otto, Oliver ; West-Foyle, Hoku ; Jacobi, Angela ; Krater, Martin ; Plak, Katarzyna ; Guck, Jochen ; Jaffee, Elizabeth ; Iglesias, Pablo A ; Anders, Robert A ; Robinson, Douglas. / Targeting mechanoresponsive proteins in pancreatic cancer : 4-hydroxyacetophenone blocks dissemination and invasion by activating MYH14. In: Cancer Research. 2019 ; Vol. 79, No. 18. pp. 4665-4678.
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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), a-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), a-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-hydroxyaceto-phenone (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. Significance: This study demonstrates that mechanoresponsive proteins become upregulated with pancreatic cancer progression and that this system of proteins can be pharma-cologically targeted to inhibit the metastatic potential of pancreatic cancer cells.",
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AU - Thomas, Dustin G.

AU - Zhu, Qingfeng

AU - DiNapoli, Kathleen T.

AU - Herbig, Maik

AU - Otto, Oliver

AU - West-Foyle, Hoku

AU - Jacobi, Angela

AU - Krater, Martin

AU - Plak, Katarzyna

AU - Guck, Jochen

AU - Jaffee, Elizabeth

AU - Iglesias, Pablo A

AU - Anders, Robert A

AU - Robinson, Douglas

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N2 - 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), a-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), a-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-hydroxyaceto-phenone (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. Significance: This study demonstrates that mechanoresponsive proteins become upregulated with pancreatic cancer progression and that this system of proteins can be pharma-cologically targeted to inhibit the metastatic potential of pancreatic cancer cells.

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