title: Biomaterial-enabled delivery of SDF-1α at the ventral side of breast cancer cells reveals a crosstalk between cell receptors to promote the invasive phenotype.
abstract: The SDF-1α chemokine (CXCL12) is a potent bioactive chemoattractant known to be involved in hematopoietic stem cell homing and cancer progression. The associated SDF-1α/CXCR4 receptor signaling is a hallmark of aggressive tumors, which can metastasize to distant sites such as lymph nodes, lung and bone. Here, we engineered a biomimetic tumoral niche made of a thin and soft polyelectrolyte film that can retain SDF-1α to present it, in a spatially-controlled manner, at the ventral side of the breast cancer cells. Matrix-bound SDF-1α but not soluble SDF-1α induced a striking increase in cell spreading and migration in a serum-containing medium, which was associated with the formation of lamellipodia and filopodia in MDA-MB231 cells and specifically mediated by CXCR4. Other Knockdown and inhibition experiments revealed that CD44, the major hyaluronan receptor, acted in concert, via a spatial coincidence, to drive a specific matrix-bound SDFα-induced cell response associated with ERK signaling. In contrast, the β1 integrin adhesion receptor played only a minor role on cell polarity. The CXCR4/CD44 mediated cellular response to matrix-bound SDF-1α involved the Rac1 RhoGTPase and was sustained solely in the presence of matrix-bound SDFα, in contrast with the transient signaling observed in response to soluble SDF-1α. Our results highlight that a biomimetic tumoral niche enables to reveal potent cellular effects and so far hidden molecular mechanisms underlying the breast cancer response to chemokines. These results open new insights for the design of future innovative therapies in metastatic cancers, by inhibiting CXCR4-mediated signaling in the tumoral niche via dual targeting of receptors (CXCR4 and CD44) or of associated signaling molecules (CXCR4 and Rac1).
authors.affiliation: CNRS UMR 5628 (LMGP), 3 parvis Louis Néel, 38016, Grenoble, France; Université Grenoble Alpes, LMGP, 3 parvis Louis Néel, 38016, Grenoble, France; FONDATION ARC, 9 rue Guy Môquet, 94803, Villejuif, France; Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China. Electronic address: xiqiuliu@hust.edu.cn.
authors.forename: Xi Qiu
authors.initials: XQ
authors.lastname: Liu
authors.affiliation: Inserm U1209, Université Grenoble Alpes, Institut Albert Bonniot, Site Santé, 38042, Grenoble cedex 9, France; CNRS UMR5309, Institute for Advanced Biosciences, Institut Albert Bonniot, 38700, La Tronche, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Fourel
authors.affiliation: CNRS UMR 5628 (LMGP), 3 parvis Louis Néel, 38016, Grenoble, France; Université Grenoble Alpes, LMGP, 3 parvis Louis Néel, 38016, Grenoble, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Dalonneau
authors.affiliation: Institut de Biologie Structurale, UMR 5075, Univ. Grenoble Alpes, CNRS, CEA, F-38027, Grenoble, France.
authors.forename: Rabia
authors.initials: R
authors.lastname: Sadir
authors.affiliation: CNRS UMR 5628 (LMGP), 3 parvis Louis Néel, 38016, Grenoble, France; Université Grenoble Alpes, LMGP, 3 parvis Louis Néel, 38016, Grenoble, France.
authors.forename: Salome
authors.initials: S
authors.lastname: Leal
authors.affiliation: Institut de Biologie Structurale, UMR 5075, Univ. Grenoble Alpes, CNRS, CEA, F-38027, Grenoble, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
authors.affiliation: CNRS UMR 5628 (LMGP), 3 parvis Louis Néel, 38016, Grenoble, France; Université Grenoble Alpes, LMGP, 3 parvis Louis Néel, 38016, Grenoble, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Weidenhaupt
authors.affiliation: Inserm U1209, Université Grenoble Alpes, Institut Albert Bonniot, Site Santé, 38042, Grenoble cedex 9, France; CNRS UMR5309, Institute for Advanced Biosciences, Institut Albert Bonniot, 38700, La Tronche, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Albiges-Rizo
authors.affiliation: CNRS UMR 5628 (LMGP), 3 parvis Louis Néel, 38016, Grenoble, France; Université Grenoble Alpes, LMGP, 3 parvis Louis Néel, 38016, Grenoble, France. Electronic address: catherine.picart@grenoble-inp.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Picart
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D016503:Drug Delivery Systems; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018960:Hyaluronan Receptors / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D020239:Receptor Cross-Talk; D019718:Receptors, CXCR4 / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D054377:Chemokine CXCL12; D018960:Hyaluronan Receptors; D019012:Integrin beta1; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D048049:Extracellular Signal-Regulated MAP Kinases; D020830:rac1 GTP-Binding Protein
keywords: Breast cancer cells; CD44; CXCR4; Chemokines; Hyaluronan; Metastasis; Polyelectrolyte multilayer films; SDF-1α/CXCL12; Tumoral niche