Manuel Patarroyo Project

Laminins and their cell-surface receptors in tumor invasion and metastasis

Tumor invasion and metastasis accounts for most cancer-related deaths but their molecular basis is poorly understood. During the metastatic cascade tumor cells migrate, survive, self-renew and proliferate via interaction with extracellular matrix proteins such as laminins. Notably, this cell-matrix interaction also contributes to chemotherapy resistance.

Laminins, a large family of αβγ heterotrimeric proteins primarily found in basement membranes (Fig. 1), are masters of normal tissue architecture, a property which is highly disrupted during tumor invasion and metastasis. In addition to their structural functions, laminins promote cell adhesion, migration, survival, self-renewal and proliferation. Over 15 laminin isoforms are presently known and their expression is developmentally regulated and cell- and tissue-specific. Laminins, via their α chain, are differentially bound by integrins and other cell-surface receptors. Although expression of laminin isoforms in tumors mostly reflects expression in their normal counterparts, distinct alterations of laminin expression and function occur during tumor invasion, particularly in epithelial-mesenchymal transition of the tumors cells and loss of the basement membrane barrier. During local dissemination and metastasis cancer cells encounter exogenous laminins in blood/lymphatic vessels, nerves, lymphoid tissue and other anatomical structures. Moreover, the tumor cells themselves are able to produce and secrete laminins and to use these endogenous molecules in an autocrine fashion.

The present research program investigates the role of laminins and their cell-surface receptors in tumor cell adhesion, migration, survival, self-renewal and proliferation as well as in tumor invasion, metastasis and chemoresistance. Both tumor-derived (endogenous) and non-tumor (exogenous) laminins are studied as well as their effect on tumor cells at different stages, including cancer stem cells and following epithelial-mesenchymal transition. Examination of laminin isoforms in tumor tissues and biological fluids has a diagnostic/prognostic potential, and antagonists of laminin-receptor interactions may constitute novel therapeutic strategies against malignant diseases.

In parallel studies the role of laminin isoforms in immune/inflammatory responses and tissue repair is also investigated.



Figure 1. The Laminin family

 

Publications

Tetraspanin CD151 and integrin α6β1 mediate platelet-enhanced endothelial colony forming cell angiogenesis.
Huang Z, Miao X, Patarroyo M, Nilsson G, Pernow J, Li N
J. Thromb. Haemost. 2016 Mar;14(3):606-18

Mesenchymal Stromal Cells for Sphincter Regeneration: Role of Laminin Isoforms upon Myogenic Differentiation.
Seeger T, Hart M, Patarroyo M, Rolauffs B, Aicher W, Klein G
PLoS ONE 2015 ;10(9):e0137419

Bacterial genotoxins promote inside-out integrin β1 activation, formation of focal adhesion complexes and cell spreading.
Levi L, Toyooka T, Patarroyo M, Frisan T
PLoS ONE 2015 ;10(4):e0124119

A laminin 511 matrix is regulated by TAZ and functions as the ligand for the α6Bβ1 integrin to sustain breast cancer stem cells.
Chang C, Goel H, Gao H, Pursell B, Shultz L, Greiner D, et al
Genes Dev. 2015 Jan;29(1):1-6

Laminins 411 and 421 differentially promote tumor cell migration via α6β1 integrin and MCAM (CD146).
Ishikawa T, Wondimu Z, Oikawa Y, Gentilcore G, Kiessling R, Egyhazi Brage S, et al
Matrix Biol. 2014 Sep;38():69-83

Monoclonal antibodies to human laminin α4 chain globular domain inhibit tumor cell adhesion and migration on laminins 411 and 421, and binding of α6β1 integrin and MCAM to α4-laminins.
Ishikawa T, Wondimu Z, Oikawa Y, Ingerpuu S, Virtanen I, Patarroyo M
Matrix Biol. 2014 Jun;36():5-14

Platelets store laminins 411/421 and 511/521 in compartments distinct from α- or dense granules and secrete these proteins via microvesicles.
Pook M, Tamming L, Padari K, Tiido T, Maimets T, Patarroyo M, et al
J. Thromb. Haemost. 2014 Apr;12(4):519-27

A novel monoclonal antibody to human laminin α5 chain strongly inhibits integrin-mediated cell adhesion and migration on laminins 511 and 521.
Wondimu Z, Omrani S, Ishikawa T, Javed F, Oikawa Y, Virtanen I, et al
PLoS ONE 2013 ;8(1):e53648

Integrin-mediated adhesion of human mesenchymal stem cells to extracellular matrix proteins adsorbed to polymer surfaces.
Dånmark S, Finne-Wistrand A, Albertsson A, Patarroyo M, Mustafa K
Biomed Mater 2012 Jun;7(3):035011

Melanoma cells produce multiple laminin isoforms and strongly migrate on α5 laminin(s) via several integrin receptors.
Oikawa Y, Hansson J, Sasaki T, Rousselle P, Domogatskaya A, Rodin S, et al
Exp. Cell Res. 2011 May;317(8):1119-33

Project Members

The project currently has vacant research positions, if you are interested please contact Manuel Patarroyo on the email address below

Professor

Manuel Patarroyo

Organizational unit: Mats Wahlgren group
E-mail: Manuel.Patarroyo@ki.se