title: Multicellular architecture of malignant breast epithelia influences mechanics.
abstract: Cell-matrix and cell-cell mechanosensing are important in many cellular processes, particularly for epithelial cells. A crucial question, which remains unexplored, is how the mechanical microenvironment is altered as a result of changes to multicellular tissue structure during cancer progression. In this study, we investigated the influence of the multicellular tissue architecture on mechanical properties of the epithelial component of the mammary acinus. Using creep compression tests on multicellular breast epithelial structures, we found that pre-malignant acini with no lumen (MCF10AT) were significantly stiffer than normal hollow acini (MCF10A) by 60%. This difference depended on structural changes in the pre-malignant acini, as neither single cells nor normal multicellular acini tested before lumen formation exhibited these differences. To understand these differences, we simulated the deformation of the acini with different multicellular architectures and calculated their mechanical properties; our results suggest that lumen filling alone can explain the experimentally observed stiffness increase. We also simulated a single contracting cell in different multicellular architectures and found that lumen filling led to a 20% increase in the "perceived stiffness" of a single contracting cell independent of any changes to matrix mechanics. Our results suggest that lumen filling in carcinogenesis alters the mechanical microenvironment in multicellular epithelial structures, a phenotype that may cause downstream disruptions to mechanosensing.
authors.affiliation: Department of Bioengineering and Biophysics Program, University of California, Berkeley, California, United States of America.
authors.forename: Gautham
authors.initials: G
authors.lastname: Venugopalan
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California, United States of America; Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: David B
authors.initials: DB
authors.lastname: Camarillo
authors.affiliation: Department of Bioengineering and Biophysics Program, University of California, Berkeley, California, United States of America.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Webster
authors.affiliation: Department of Bioengineering and Biophysics Program, University of California, Berkeley, California, United States of America.
authors.forename: Clay D
authors.initials: CD
authors.lastname: Reber
authors.affiliation: Department of Mathematics, University of California, Berkeley, California, United States of America; Department of Mathematics, Lawrence Berkeley Laboratory, Berkeley, California, United States of America.
authors.forename: James A
authors.initials: JA
authors.lastname: Sethian
authors.affiliation: Departments of Surgery, Anatomy, Bioengineering, and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America; Center for Bioengineering and Tissue Regeneration, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.affiliation: Department of Bioengineering and Biophysics Program, University of California, Berkeley, California, United States of America; Physical Biosciences Division, Lawrence Berkeley Laboratory, Berkeley, California, United States of America.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Fletcher
authors.affiliation: Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Hana
authors.initials: H
authors.lastname: El-Samad
authors.affiliation: Department of Mathematics, Lawrence Berkeley Laboratory, Berkeley, California, United States of America; School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Chris H
authors.initials: CH
authors.lastname: Rycroft
mesh_terms: D061354:Acinar Cells / Q000166:cytology / Q000473:pathology; D001696:Biomechanical Phenomena; D001940:Breast / Q000166:cytology* / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D004548:Elasticity; D004847:Epithelial Cells / Q000166:cytology* / Q000473:pathology*; D006801:Humans; D055595:Mechanical Phenomena; D008954:Models, Biological; D015398:Signal Transduction; D059016:Tumor Microenvironment
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