Publications

Directed differentiation of human induced pluripotent stem cells into mature kidney podocytes and establishment of a Glomerulus Chip

Musah S., Dimitrakakis N., Camacho D.M., Church G.M., Ingber D.E. Nature Protocols, 2018

With the use of laminin 511 coating, the authors have developed a detailed protocol for the directed differentiation of human iPS cells into mature, post-mitotic kidney glomerular podocytes with high (>90%) efficiency within 26 d and under chemically defined conditions, without genetic manipulations or subpopulation selection. They also describe how these iPS cell-derived podocytes may be induced to form within a microfluidic organ-on-a-chip culture device to build a human kidney Glomerulus Chip that mimics the structure and function of the kidney glomerular capillary wall in vitro.

The opposing roles of laminin-binding integrins in cancer

Ramovs V., te Molder L., Sonnenberg A. Matrix Biology, 2016

In this review the authors discuss the dual role of the laminin-binding integrins α3β1 and α6β4 in tumor development and progression and examine the factors and mechanisms involved in these opposing effects. 

Ligand-binding specificities of laminin-binding integrins: a comprehensive survey of laminin-integrin interactions using recombinant alpha3beta1, alpha6beta1, alpha7beta1 and alpha6beta4 integrins

Nishiuchi et al.
Matrix Biol., 2006 

Selection and Characterization of an α6β4 Integrin blocking DNA Aptamer

Berg K., Lange T., Mittelberger F., Schumacher U., Hahn U.Molecular Therapy—Nucleic Acids, 2016

Cancer cells use the α6β4 integrin/laminin-332 interaction to activate signaling pathways promoting tumor cell growth, invasion and metastasis, the inhibition of this interaction is of high therapeutic interest. Here, the authors report on the selection of a DNA aptamer inhibiting the interaction between α6β4 integrin and laminin-332. This Integrin α6β4-specific DNA Aptamer inhibits the adhesion of prostate cancer cells (PC-3) to laminin-332 with an IC50 value of 149 nmol/l. the aptamer was internalized into PC- 3-cells. Further characterization showed specificity to α6 integrins and a half-life in the murine blood plasma of 6 hours.

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 Biology, 2014

α4-Laminins, such as laminins -411 and -421, are mesenchymal laminins expressed by vascular and lymphatic endothelial cells, leukocytes and other normal cell types. These laminins are recognized by α6β1 and α6β4 integrins and MCAM (CD146) and promote adhesion and migration of the cells. α4-Laminins are also expressed and secreted by some tumor cells and strongly promote tumor cell migration. Moreover, the abluminal side of blood and/or lymphatic vessels and the nerve perineurium, common tracks of tumor cell dissemination, express α4-laminins, and these laminin isoforms, when expressed in the stroma, may contribute to tumor invasion. In the present study, we examined ten mAbs to human laminin α4 chain for their reactivity with the isolated laminin α4 globular domain, their ability to inhibit tumor cell adhesion and migration on laminin-411 and -421, and their effect on the binding of α6β1 integrin and MCAM to both α4-laminins. The results indicate that mAbs to the laminin α4 globular domain are able to inhibit tumor cell adhesion and migration on laminin-411 and -421 and that α6β1 integrin and MCAM bind α4-laminins at very close sites on the globular domain. These reagents contribute to a better understanding of the biology of α4-laminins and may have a therapeutic potential in malignant and inflammatory diseases.

Laminin-332 sustains chemoresistance and quiescence as part of the human hepatic cancer stem cell niche

Govaere O. et al. Journal of hepatology, 2015

This study demonstrates that tumor behavior is plastic and depends on the microenvironment of the tumor cell. The authors identified an important role for laminin-332 - more specifically its gamma2-chain - as part of the specialized cancer stem cell niche in maintaining and supporting stemness, e.g. quiescence and chemo-resistance. Laminin-332 not only protects hepatic cancer cells against chemotherapy but even stimulates cell proliferation upon sorafenib exposure. Therefore, monoclonal antibody treatment targeting the gamma2-chain of laminin-332 could provide an innovative therapy for hepatic cancer.

Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma

Bald T., Quast T., Landsberg J., Rogava M., Glodde n., Lopez-Ramos D., Kohlmeyer J., Riesenberg S., van den Boorn-Konijnenberg D.,  Hömig-Hölzel C., Reuten R., Schadow B., Weighardt H., Wenzel D., Helfrich I., Schadendorf D., Bloch W., Bianchi M.E., Lugassy C., Barnhill R.L., Koch M., Fleischmann B.K., Förster I., Kastenmüller W., Kolanus W., Hölzel M., Gaffal E., Tüting T. Nature Letter. 2014

The authors report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression. UV irradiation enhanced the expansion of tumor cells along abluminal blood vessel surfaces and increased the number of lung metastases, depended on the recruitment and activation of neutrophils. In a static cell adhesion assays, cells were allowed to adhere to various matrices: fibronectin-1, collagen type I, collagen type IV, laminin-111 (Sigma), laminin-411 or laminin-511. An inflammatory environment promotes the ability of mouse and human melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces.

Laminin Interactions with Head and Neck Cancer Cells under Low Fluid Shear Conditions Lead to Integrin Activation and Binding

Fennewald S.M., Kantara C., Sastry S.K., Resto V.AJournal of biological chemistry, 2012

Lymphatic metastasis of cancer cells involves movement from the primary tumor site to the lymph node, where the cells must be able to productively lodge and grow. Head and neck squamous cell carcinoma (HNSCC) cell lines cultured on placental laminin (laminin-511 is the major laminin), laminin-332 purified from human foreskin keratinocytes and human recombinant laminin-511, -211, -111, and -411. HNSCC cell lines bound to laminin-511 and -211 but also to -411 to a lower extent, under lymphodynamic low shear stress (0.07 dynes/cm2), consistent with lymph flow. Binding only occurred in the presence of shear stress and not in the absence of flow. The authors conclude that B1 integrins mediate tumor cell/lymph node interactions active under lymphodynamic flow. These interactions may drive growth and immunomodulation in this niche.

Gelatine methacrylamide-based hydrogels – an alternative 3D cancer cell culture system

Kaemmerer E., Melchels F.P.W, Holzapfel B.M, Meckel T., Hutmacher D.W., Loessner D. Acta Biomaterialia, 2014

The authors present a 3D biomaterial platform for the analysis of ovarian cancer spheroid growth that is an efficient semi-synthetic alternative, combining native ECM components and tunable matrix properties, resulting in higher reproducibility, less complexity and better comparability between different groups than traditional cell monolayer approaches. In this study, gelatine methacrylamide-based hydrogels (GelMA) with added LN-411 were established as in vitro and in vivo spheroid-based 3D cancer models.

Laminins and cancer stem cells: Partners in crime?

Qin Y., Rodin S., Simonson O.E., Hollande F. Seminars in Cancer Biology, 2016

A review that discusses the role of laminin as a regulator of cancer stem cells, in tumor progression and drug resistance. A growing body of literature suggests that laminins may act as regulators of cancer stem cells, a tumor cell subpopulation that plays an instrumental role in long-term cancer maintenance, metastasis development, and therapeutic resistance. The accumulating evidence in this emerging research area suggests that laminins represent potential therapeutic targets for anti-cancer treatments against cancer stem cells and that they may be used as predictive and prognostic markers to inform clinical management and improve patient survival.