title: The cancer glycocalyx mechanically primes integrin-mediated growth and survival.
abstract: Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function.
authors.affiliation: 1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA [3] School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, USA [4] Laboratory for Atomic and Solid State Physics and Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Paszek
authors.affiliation: 1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: DuFort
authors.affiliation: 1] Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, F-33000 Bordeaux, France [2] CNRS, Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, F-33000 Bordeaux, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rossier
authors.affiliation: 1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Bainer
authors.affiliation: Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA.
authors.forename: Janna K
authors.initials: JK
authors.lastname: Mouw
authors.affiliation: 1] Department of Chemistry, University of California, Berkeley, California 94720, USA [2] The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [3] Department of Chemistry and Biochemistry, University of California, San Diego, California 92093, USA.
authors.forename: Kamil
authors.initials: K
authors.lastname: Godula
authors.affiliation: Department of Chemistry, University of California, Berkeley, California 94720, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Hudak
authors.affiliation: Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA.
authors.forename: Jonathon N
authors.initials: JN
authors.lastname: Lakins
authors.affiliation: 1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Wijekoon
authors.affiliation: 1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Cassereau
authors.affiliation: 1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Rubashkin
authors.affiliation: 1] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA [2] Division of Hematology/Oncology, University of California, San Francisco, California 94143, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Magbanua
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.
authors.forename: Kurt S
authors.initials: KS
authors.lastname: Thorn
authors.affiliation: National High Magnetic Field Laboratory and Department of Biological Science, The Florida State University, Tallahassee, Florida 32310, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Davidson
authors.affiliation: 1] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA [2] Division of Hematology/Oncology, University of California, San Francisco, California 94143, USA.
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: 1] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA [2] Division of Hematology/Oncology, University of California, San Francisco, California 94143, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.affiliation: Departments of Chemical and Biomolecular Engineering and Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hammer
authors.affiliation: 1] Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, F-33000 Bordeaux, France [2] CNRS, Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, F-33000 Bordeaux, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Giannone
authors.affiliation: 1] Department of Chemistry, University of California, Berkeley, California 94720, USA [2] Department of Molecular Biology, University of California, Berkeley, California 94720, USA [3] Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Bertozzi
authors.affiliation: 1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA [3] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA [4] Departments of Anatomy and Bioengineering and Therapeutic Sciences and Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
mesh_terms: D000818:Animals; D001940:Breast / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005347:Fibroblasts; D019276:Glycocalyx / Q000737:chemistry / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D055767:Immobilized Proteins / Q000737:chemistry / Q000378:metabolism; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D018396:Mucin-1 / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009360:Neoplastic Cells, Circulating; D011485:Protein Binding; D011956:Receptors, Cell Surface
chemical_list: D006023:Glycoproteins; D055767:Immobilized Proteins; D016023:Integrins; D018396:Mucin-1; D011956:Receptors, Cell Surface