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Open AccessArticle

The Interaction between Laminin-332 and α3β1 Integrin Determines Differentiation and Maintenance of CAFs, and Supports Invasion of Pancreatic Duct Adenocarcinoma Cells

1
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Waldeyerstr. 15, 48149 Münster, Germany
2
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany
3
Department of General, Visceral and Transplantation Surgery, University Hospital Münster, Albert-Schweitzer-Campus 1 (W1), 48149 Münster, Germany
4
Biotech Research and Innovation Center (BRIC), University of Copenhagen, Ole Maaløes vej 5, 2200 Copenhagen, Denmark
*
Author to whom correspondence should be addressed.
Present address: ICME HealthCare, Klopstockstraße 27, 22765 Hamburg, Germany.
Cancers 2019, 11(1), 14; https://doi.org/10.3390/cancers11010014
Received: 26 October 2018 / Revised: 3 December 2018 / Accepted: 18 December 2018 / Published: 21 December 2018
(This article belongs to the Special Issue The Role of Integrins in Cancer)
Ranking among the most lethal tumour entities, pancreatic duct adenocarcinoma cells invade neighbouring tissue resulting in high incidence of metastasis. They are supported by tumour stroma fibroblasts which have undergone differentiation into cancer-associated fibroblasts (CAFs). Stiffness of cell substratum, cytokines, such as transforming growth factor-β (TGF-β), and stromal matrix proteins, such as laminin-332, are factors which promote CAF differentiation. In a spheroid culture system, differentiation of CAFs was analysed for laminin-332 production, laminin-binding integrin repertoire, adhesion and migration behaviour, and, in heterospheroids, for their interplay with the pancreatic duct adenocarcinoma AsPC-I cells. Our data reveal that CAFs produce laminin-332 thus contributing to its ectopic deposition within the tumour stroma. Moreover, CAF differentiation correlates with an increased expression of α3β1 integrin, the principal laminin-332-receptor. Beyond its role as novel CAF marker protein, integrin α3β1 crucially determines differentiation and maintenance of the CAF phenotype, as knock-out of the integrin α3 subunit reversed the CAF differentiated state. AsPC-I cells co-cultured in heterospheroids with integrin α3-deficient CAFs invaded less than from heterospheroids with wild-type CAFs. This study highlights the role of integrin α3β1 integrin-laminin-332 interaction of CAFs which promotes and sustains differentiation of CAFs and promotes carcinoma invasion. View Full-Text
Keywords: pancreatic cancer; cancer-associated fibroblasts (CAF); differentiation; laminin-332; integrin α3β1; spheroid culture; invasion pancreatic cancer; cancer-associated fibroblasts (CAF); differentiation; laminin-332; integrin α3β1; spheroid culture; invasion
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MDPI and ACS Style

Martins Cavaco, A.C.; Rezaei, M.; Caliandro, M.F.; Martins Lima, A.; Stehling, M.; Dhayat, S.A.; Haier, J.; Brakebusch, C.; Eble, J.A. The Interaction between Laminin-332 and α3β1 Integrin Determines Differentiation and Maintenance of CAFs, and Supports Invasion of Pancreatic Duct Adenocarcinoma Cells. Cancers 2019, 11, 14. https://doi.org/10.3390/cancers11010014

AMA Style

Martins Cavaco AC, Rezaei M, Caliandro MF, Martins Lima A, Stehling M, Dhayat SA, Haier J, Brakebusch C, Eble JA. The Interaction between Laminin-332 and α3β1 Integrin Determines Differentiation and Maintenance of CAFs, and Supports Invasion of Pancreatic Duct Adenocarcinoma Cells. Cancers. 2019; 11(1):14. https://doi.org/10.3390/cancers11010014

Chicago/Turabian Style

Martins Cavaco, Ana C.; Rezaei, Maryam; Caliandro, Michele F.; Martins Lima, Augusto; Stehling, Martin; Dhayat, Sameer A.; Haier, Jörg; Brakebusch, Cord; Eble, Johannes A. 2019. "The Interaction between Laminin-332 and α3β1 Integrin Determines Differentiation and Maintenance of CAFs, and Supports Invasion of Pancreatic Duct Adenocarcinoma Cells" Cancers 11, no. 1: 14. https://doi.org/10.3390/cancers11010014

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