title: Loss of myoferlin redirects breast cancer cell motility towards collective migration.
abstract: Cell migration plays a central role in the invasion and metastasis of tumors. As cells leave the primary tumor, they undergo an epithelial to mesenchymal transition (EMT) and migrate as single cells. Epithelial tumor cells may also migrate in a highly directional manner as a collective group in some settings. We previously discovered that myoferlin (MYOF) is overexpressed in breast cancer cells and depletion of MYOF results in a mesenchymal to epithelial transition (MET) and reduced invasion through extracellular matrix (ECM). However, the biomechanical mechanisms governing cell motility during MYOF depletion are poorly understood. We first demonstrated that lentivirus-driven shRNA-induced MYOF loss in MDA-MB-231 breast cancer cells (MDA-231(MYOF-KD)) leads to an epithelial morphology compared to the mesenchymal morphology observed in control (MDA-231(LTVC)) and wild-type cells. Knockdown of MYOF led to significant reductions in cell migration velocity and MDA-231(MYOF-KD) cells migrated directionally and collectively, while MDA-231(LTVC) cells exhibited single cell migration. Decreased migration velocity and collective migration were accompanied by significant changes in cell mechanics. MDA-231(MYOF-KD) cells exhibited a 2-fold decrease in cell stiffness, a 2-fold increase in cell-substrate adhesion and a 1.5-fold decrease in traction force generation. In vivo studies demonstrated that when immunocompromised mice were implanted with MDA-231(MYOF-KD) cells, tumors were smaller and demonstrated lower tumor burden. Moreover, MDA-231(MYOF-KD) tumors were highly circularized and did not invade locally into the adventia in contrast to MDA-231(LTVC)-injected animals. Thus MYOF loss is associated with a change in tumor formation in xenografts and leads to smaller, less invasive tumors. These data indicate that MYOF, a previously unrecognized protein in cancer, is involved in MDA-MB-231 cell migration and contributes to biomechanical alterations. Our results indicate that changes in biomechanical properties following loss of this protein may be an effective way to alter the invasive capacity of cancer cells.
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Leonithas I
authors.initials: LI
authors.lastname: Volakis
authors.affiliation: Department of Obstetrics & Gynecology (Division of Maternal-Fetal Medicine and Laboratory of Perinatal Research), The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Ruth
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Obstetrics & Gynecology (Division of Maternal-Fetal Medicine and Laboratory of Perinatal Research), The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Ackerman
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Cosmin
authors.initials: C
authors.lastname: Mihai
authors.affiliation: Department of Obstetrics & Gynecology (Division of Maternal-Fetal Medicine and Laboratory of Perinatal Research), The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Meagan
authors.initials: M
authors.lastname: Bechel
authors.affiliation: Department of Obstetrics & Gynecology (Division of Maternal-Fetal Medicine and Laboratory of Perinatal Research), The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Taryn L
authors.initials: TL
authors.lastname: Summerfield
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Ahn
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, United States of America ; Department of Material Science Engineering, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Powell
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Zielinski
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, United States of America ; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Samir N
authors.initials: SN
authors.lastname: Ghadiali
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, United States of America ; Department of Obstetrics & Gynecology (Division of Maternal-Fetal Medicine and Laboratory of Perinatal Research), The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Kniss
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics*
chemical_list: D002135:Calcium-Binding Proteins; C415584:MYOF protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins