scholarly journals A Drosophila RNAi screen reveals conserved glioblastoma-related adhesion genes that regulate collective cell migration

2021 ◽  
Author(s):  
Nirupama Kotian ◽  
Katie M Troike ◽  
Kristen N Curran ◽  
Justin D Lathia ◽  
Jocelyn A McDonald
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Invasion ◽  
Brain Parenchyma ◽  
Cell Junction ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Bioinformatics Analyses ◽  
Border Cell ◽  
Matrix Cell

Abstract Migrating cell collectives are key to embryonic development but also contribute to invasion and metastasis of a variety of cancers. Cell collectives can invade deep into tissues, leading to tumor progression and resistance to therapies. Collective cell invasion is also observed in the lethal brain tumor glioblastoma, which infiltrates the surrounding brain parenchyma leading to tumor growth and poor patient outcomes. Drosophila border cells, which migrate as a small cell cluster in the developing ovary, are a well-studied and genetically accessible model used to identify general mechanisms that control collective cell migration within native tissue environments. Most cell collectives remain cohesive through a variety of cell-cell adhesion proteins during their migration through tissues and organs. In this study, we first identified cell adhesion, cell matrix, cell junction, and associated regulatory genes that are expressed in human brain tumors. We performed RNAi knockdown of the Drosophila orthologs in border cells to evaluate if migration and/or cohesion of the cluster was impaired. From this screen, we identified eight adhesion-related genes that disrupted border cell collective migration upon RNAi knockdown. Bioinformatics analyses further demonstrated that subsets of the orthologous genes were elevated in the margin and invasive edge of human glioblastoma patient tumors. These data together show that conserved cell adhesion and adhesion regulatory proteins with potential roles in tumor invasion also modulate collective cell migration. This dual screening approach for adhesion genes linked to glioblastoma and border cell migration thus may reveal conserved mechanisms that drive collective tumor cell invasion.

scholarly journals A Drosophila RNAi screen reveals conserved glioblastoma-related adhesion genes that regulate collective cell migration

2021 ◽  
Author(s):  
Nirupama Kotian ◽  
Katie M. Troike ◽  
Kristen N. Curran ◽  
Justin D. Lathia ◽  
Jocelyn A McDonald
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Invasion ◽  
Brain Parenchyma ◽  
Cell Junction ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Bioinformatics Analyses ◽  
Border Cell ◽  
Cell Adhesion Proteins

Migrating cell collectives are key to embryonic development but also contribute to invasion and metastasis of a variety of cancers. Cell collectives can invade deep into tissues, leading to tumor progression and resistance to therapies. Collective cell invasion is also observed in the lethal brain tumor glioblastoma, which infiltrates the surrounding brain parenchyma leading to tumor growth and poor patient outcomes. Drosophila border cells, which migrate as a small cell cluster in the developing ovary, are a well-studied and genetically accessible model used to identify general mechanisms that control collective cell migration within native tissue environments. Most cell collectives remain cohesive through a variety of cell-cell adhesion proteins during their migration through tissues and organs. In this study, we first identified cell adhesion, cell junction, and associated regulatory genes that are expressed in human brain tumors. We performed RNAi knockdown of the Drosophila orthologs in border cells to evaluate if migration and/or cohesion of the cluster was impaired. From this screen, we identified eight adhesion genes that disrupted border cell collective migration upon RNAi knockdown. Bioinformatics analyses further demonstrated that subsets of the orthologous genes were elevated in the margin and invasive edge of human glioblastoma patient tumors. These data together show that conserved cell adhesion and adhesion regulatory proteins with potential roles in tumor invasion also modulate collective cell migration. This dual screening approach for adhesion genes linked to glioblastoma and border cell migration thus may reveal conserved mechanisms that drive collective tumor cell invasion.

scholarly journals Collective cell migration in development

2016 ◽  
Vol 212 (2) ◽  
pp. 143-155 ◽  
Author(s):  
Elena Scarpa ◽  
Roberto Mayor
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Collective Cell Migration ◽  
Germ Layer ◽  
Collective Migration ◽  
Developmental Models ◽  
Border Cell ◽  
Guidance Cues ◽  
Tracheal Branching

During embryonic development, tissues undergo major rearrangements that lead to germ layer positioning, patterning, and organ morphogenesis. Often these morphogenetic movements are accomplished by the coordinated and cooperative migration of the constituent cells, referred to as collective cell migration. The molecular and biomechanical mechanisms underlying collective migration of developing tissues have been investigated in a variety of models, including border cell migration, tracheal branching, blood vessel sprouting, and the migration of the lateral line primordium, neural crest cells, or head mesendoderm. Here we review recent advances in understanding collective migration in these developmental models, focusing on the interaction between cells and guidance cues presented by the microenvironment and on the role of cell–cell adhesion in mechanical and behavioral coupling of cells within the collective.

scholarly journals Tousled-like kinase regulates cytokine-mediated communication between cooperating cell types during collective border cell migration

2016 ◽  
Vol 27 (1) ◽  
pp. 12-19 ◽  
Author(s):  
Wenjuan Xiang ◽  
Dabing Zhang ◽  
Denise J. Montell
Keyword(s):  
Cell Migration ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Cell Types ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Stat Signaling ◽  
Border Cell Migration

Collective cell migration is emerging as a major contributor to normal development and disease. Collective movement of border cells in the Drosophila ovary requires cooperation between two distinct cell types: four to six migratory cells surrounding two immotile cells called polar cells. Polar cells secrete a cytokine, Unpaired (Upd), which activates JAK/STAT signaling in neighboring cells, stimulating their motility. Without Upd, migration fails, causing sterility. Ectopic Upd expression is sufficient to stimulate motility in otherwise immobile cells. Thus regulation of Upd is key. Here we report a limited RNAi screen for nuclear proteins required for border cell migration, which revealed that the gene encoding Tousled-like kinase (Tlk) is required in polar cells for Upd expression without affecting polar cell fate. In the absence of Tlk, fewer border cells are recruited and motility is impaired, similar to inhibition of JAK/STAT signaling. We further show that Tlk in polar cells is required for JAK/STAT activation in border cells. Genetic interactions further confirmed Tlk as a new regulator of Upd/JAK/STAT signaling. These findings shed light on the molecular mechanisms regulating the cooperation of motile and nonmotile cells during collective invasion, a phenomenon that may also drive metastatic cancer.

scholarly journals Fascin limits Myosin activity within Drosophila border cells to control substrate stiffness and promote migration

2021 ◽  
Author(s):  
Maureen C. Lamb ◽  
Chathuri P. Kaluarachchi ◽  
Thiranjeewa I. Lansakara ◽  
Yiling Lan ◽  
Alexei V. Tivanski ◽  
...  
Keyword(s):  
Cell Migration ◽  
Nurse Cell ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Substrate Stiffness ◽  
Cell Stiffness ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Border Cell Migration

AbstractA key regulator of collective cell migrations, which drive development and cancer metastasis, is substrate stiffness. Increased substrate stiffness promotes migration and is controlled by Myosin. Using Drosophila border cell migration as a model of collective cell migration, we identify, for the first time, that the actin bundling protein Fascin limits Myosin activity in vivo. Loss of Fascin results in: increased activated Myosin on the border cells and their substrate, the nurse cells; decreased border cell Myosin dynamics; and increased nurse cell stiffness as measured by atomic force microscopy. Reducing Myosin restores on-time border cell migration in fascin mutant follicles. Further, Fascin’s actin bundling activity is required to limit Myosin activation. Surprisingly, we find that Fascin regulates Myosin activity in the border cells to control nurse cell stiffness to promote migration. Thus, these data shift the paradigm from a substrate stiffness-centric model of regulating migration, to uncover that collectively migrating cells play a critical role in controlling the mechanical properties of their substrate in order to promote their own migration. This new means of mechanical regulation of migration is likely conserved across contexts and organisms, as Fascin and Myosin are common regulators of cell migration.

scholarly journals Src42A required for collective border cell migration in vivo

2017 ◽  
Author(s):  
Yasmin Sallak ◽  
Alba Yurani Torres ◽  
Hongyan Yin ◽  
Denise Montell
Keyword(s):  
Cell Migration ◽  
Cell Junctions ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Border Cell Migration ◽  
And Migration ◽  
Drosophila Ovary ◽  
E Cadherin

AbstractThe tyrosine kinase Src is over-expressed in numerous human cancers and is associated with poor prognosis. While Src has been extensively studied, its contributions to collective cell migration in vivo remain incompletely understood. Here we show that Src42A, but not Src64, is required for the specification and migration of the border cells in the Drosophila ovary, a well-developed and genetically tractable in vivo cell migration model. We found active Src42A enriched at border cell/nurse cell interfaces, where E-cadherin is less abundant, and depleted from border cell/border cell and border cell/polar cell junctions where E-cadherin is more stable, whereas total Src42A protein co-localizes with E-cadherin. Over-expression of wild type Src42A mislocalized Src activity and prevented border cell migration. Constitutively active or kinase dead forms of Src42A also impeded border cells. These findings establish border cells as a model for investigating the mechanisms of action of Src in cooperative, collective, cell-on-cell migration in vivo.

scholarly journals Protein phosphatase 1 activity controls a balance between collective and single cell modes of migration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yujun Chen ◽  
Nirupama Kotian ◽  
George Aranjuez ◽  
Lin Chen ◽  
C Luke Messer ◽  
...  
Keyword(s):  
Cell Migration ◽  
Single Cell ◽  
Protein Phosphatase ◽  
Single Cells ◽  
Cell Junctions ◽  
Protein Phosphatase 1 ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
And Migration

Collective cell migration is central to many developmental and pathological processes. However, the mechanisms that keep cell collectives together and coordinate movement of multiple cells are poorly understood. Using the Drosophila border cell migration model, we find that Protein phosphatase 1 (Pp1) activity controls collective cell cohesion and migration. Inhibition of Pp1 causes border cells to round up, dissociate, and move as single cells with altered motility. We present evidence that Pp1 promotes proper levels of cadherin-catenin complex proteins at cell-cell junctions within the cluster to keep border cells together. Pp1 further restricts actomyosin contractility to the cluster periphery rather than at individual internal border cell contacts. We show that the myosin phosphatase Pp1 complex, which inhibits non-muscle myosin-II (Myo-II) activity, coordinates border cell shape and cluster cohesion. Given the high conservation of Pp1 complexes, this study identifies Pp1 as a major regulator of collective versus single cell migration.

scholarly journals Protein Phosphatase 1 activity controls a balance between collective and single cell modes of migration

2019 ◽  
Author(s):  
Yujun Chen ◽  
Nirupama Kotian ◽  
George Aranjuez ◽  
Lin Chen ◽  
C. Luke Messer ◽  
...  
Keyword(s):  
Cell Migration ◽  
Single Cell ◽  
Protein Phosphatase ◽  
Single Cells ◽  
Cell Junctions ◽  
Protein Phosphatase 1 ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Cell Cell

AbstractCollective cell migration is central to many developmental and pathological processes. However, the mechanisms that keep cell collectives together and coordinate movement of multiple cells are poorly understood. Using the Drosophila border cell migration model, we find that Protein phosphatase 1 (Pp1) activity controls collective cell cohesion and migration. Inhibition of Pp1 causes border cells to round up, dissociate, and move as single cells with altered motility. We present evidence that Pp1 promotes proper levels of cadherin-catenin complex proteins at cell-cell junctions within the cluster to keep border cells together. Pp1 further restricts actomyosin contractility to the cluster periphery rather than at internal cell-cell contacts. We show that the myosin phosphatase Pp1 complex, which inhibits non-muscle myosin-II (Myo-II) activity, coordinates border cell shape and cluster cohesion. Given the high conservation of Pp1 complexes, this study identifies Pp1 as a major regulator of collective versus single cell migration.

scholarly journals Fascin regulates protrusions and delamination to mediate invasive, collective cell migration in vivo

2019 ◽  
Author(s):  
Maureen C. Lamb ◽  
Kelsey K. Anliker ◽  
Tina L. Tootle
Keyword(s):  
Cell Migration ◽  
Cancer Metastasis ◽  
Collective Cell Migration ◽  
Nurse Cells ◽  
Border Cells ◽  
Border Cell ◽  
Migration Data ◽  
Border Cell Migration

AbstractFascin is an actin bundling protein that is essential for developmental cell migrations and promotes cancer metastasis. In addition to bundling actin, Fascin has several actin-independent roles. Border cell migration during Drosophila oogenesis provides an excellent model to study Fascin’s various roles during invasive, collective cell migration. Border cell migration requires Fascin. Fascin functions not only within the migrating border cells, but also within the nurse cells, the substrate for this migration. Loss of Fascin results in increased, shorter and mislocalized protrusions during migration. Data supports the model that Fascin promotes the activity of Enabled, an actin elongating factor, to regulate migration. Additionally, loss of Fascin inhibits border cell delamination. These defects are partially due to altered E-cadherin localization in the border cells; this is predicted to be an actin-independent role of Fascin. Overall, Fascin is essential for multiple aspects of this invasive, collective cell migration, and functions in both actin-dependent and -independent manners. These findings have implications beyond Drosophila, as border cell migration has emerged as a model to study mechanisms mediating cancer metastasis.

scholarly journals Fascin limits Myosin activity within Drosophila border cells to control substrate stiffness and promote migration

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Maureen C Lamb ◽  
Chathuri P Kaluarachchi ◽  
Thiranjeewa I Lansakara ◽  
Samuel Q Mellentine ◽  
Yiling Lan ◽  
...  
Keyword(s):  
Cell Migration ◽  
Nurse Cell ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Substrate Stiffness ◽  
Cell Stiffness ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Border Cell Migration

A key regulator of collective cell migrations, which drive development and cancer metastasis, is substrate stiffness. Increased substrate stiffness promotes migration and is controlled by Myosin. Using Drosophila border cell migration as a model of collective cell migration, we identify, for the first time, that the actin bundling protein Fascin limits Myosin activity in vivo. Loss of Fascin results in: increased activated Myosin on the border cells and their substrate, the nurse cells; decreased border cell Myosin dynamics; and increased nurse cell stiffness as measured by atomic force microscopy. Reducing Myosin restores on-time border cell migration in fascin mutant follicles. Further, Fascin’s actin bundling activity is required to limit Myosin activation. Surprisingly, we find that Fascin regulates Myosin activity in the border cells to control nurse cell stiffness to promote migration. Thus, these data shift the paradigm from a substrate stiffness-centric model of regulating migration, to uncover that collectively migrating cells play a critical role in controlling the mechanical properties of their substrate in order to promote their own migration. This understudied means of mechanical regulation of migration is likely conserved across contexts and organisms, as Fascin and Myosin are common regulators of cell migration.

scholarly journals Septins are essential for protrusion and detachment in collective border cell migration

2021 ◽  
Author(s):  
Allison M Gabbert ◽  
James Mondo ◽  
Joseph P Campanale ◽  
Denise J Montell
Keyword(s):  
Cell Migration ◽  
Cell Model ◽  
Myosin Ii ◽  
Follicle Cells ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Nonmuscle Myosin ◽  
Border Cell ◽  
Nonmuscle Myosin Ii

Collective cell migration is prevalent throughout development and common in metastatic tumors, yet this process is not fully understood. In this study, we explore the role of septins (Sep) in collective cell migration, using the Drosophila border cell model. We show that Sep2 and Pnut are expressed in migrating border cells and Sep1, 2, 4, and Peanut (Pnut) are required for migration. Pnut stability depends on the expression of Sep1 and Sep2 in epithelial follicle cells and migratory border cells. We show that knockdown of septins prevents normal protrusion and detachment behaviors. High resolution Airyscan imaging reveals Pnut localization in rings at the base of protrusions. While septins function independently of Cdc42, they colocalize dynamically with nonmuscle myosin II. We suggest that septin polymers may stabilize growing protrusions until sufficient myosin is recruited to retract them.

Sign in / Sign up

Export Citation Format

Share Document