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Solid Stress Facilitates Fibroblasts Activation to Promote Pancreatic Cancer Cell Migration

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Abstract

Pancreatic fibroblasts are continuously gaining ground as an important component of tumor microenvironment that dynamically interact with cancer cells to promote tumor progression. In addition, these tumor-infiltrated fibroblasts can acquire an activated phenotype and produce excessive amounts of extracellular matrix creating a highly dense stroma, a situation known as desmoplasia. Desmoplasia, along with the uncontrolled proliferation of cancer cells, leads to the development of compressive forces within the tumor, generating the so-called solid stress. Solid stress is previously shown to affect cancer cell proliferation and migration, however there is no pertinent study taking into account the effects of solid stress on fibroblasts and whether these effects contribute to tumor progression. In this work, we applied a defined compressive stress on pancreatic fibroblasts, similar in magnitude to that experienced by cells in native pancreatic tumors. Our results suggest that solid stress stimulates fibroblasts activation and strongly upregulates Growth Differentiation Factor-15 (GDF15) expression. Moreover, co-culture of compression-induced activated fibroblasts with pancreatic cancer cells significantly promotes cancer cell migration, which is inhibited by shRNA-mediated silencing of GDF15 in fibroblasts. Conclusively, our findings highlight the involvement of biophysical factors, such as solid stress, in tumor progression and malignancy revealing a novel role for GDF15.

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Acknowledgments

This work has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC Grant Agreement No. 336839-ReEngineeringCancer.

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Authors and Affiliations

  1. Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, P.O. Box 20537, 1678, Nicosia, Cyprus

    Maria Kalli, Panagiotis Papageorgis, Vasiliki Gkretsi & Triantafyllos Stylianopoulos

  2. Department of Life Sciences, European University Cyprus, Nicosia, Cyprus

    Panagiotis Papageorgis & Vasiliki Gkretsi

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  1. Maria Kalli
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  2. Panagiotis Papageorgis
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Correspondence to Triantafyllos Stylianopoulos.

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Associate Editor Konstantinos Konstantopoulos oversaw the review of this article.

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Kalli, M., Papageorgis, P., Gkretsi, V. et al. Solid Stress Facilitates Fibroblasts Activation to Promote Pancreatic Cancer Cell Migration. Ann Biomed Eng 46, 657–669 (2018). https://doi.org/10.1007/s10439-018-1997-7

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