Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of Glioblastoma-Initiating Cells that Infiltrate Peritumoral Tissue

Patricia Ruiz-Ontanon; Jose L. Orgaz; Beatriz Aldaz; Alberto Elosegui-Artola; Juan Martino; Maria T. Berciano; Juan A. Montero; Lara Grande; Lorena Nogueira; Santiago Diaz-Moralli; Azucena Esparis-Ogando; Alfonso Vazquez-Barquero; Miguel Lafarga; Atanasio Pandiella; Marta Cascante; Victor Segura; Jose A. Martinez-Climent; Vicky Sanz Moreno; Jose L. Fernandez-Luna

doi:10.1002/stem.1349

Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of Glioblastoma-Initiating Cells that Infiltrate Peritumoral Tissue

Patricia Ruiz-Ontanon, Jose L. Orgaz, Beatriz Aldaz, Alberto Elosegui-Artola, Juan Martino, Maria T. Berciano, Juan A. Montero, Lara Grande, Lorena Nogueira, Santiago Diaz-Moralli, Azucena Esparis-Ogando, Alfonso Vazquez-Barquero, Miguel Lafarga, Atanasio Pandiella, Marta Cascante, Victor Segura, Jose A. Martinez-Climent, Vicky Sanz Moreno, Jose L. Fernandez-Luna^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

79 Citations (Scopus)

Abstract

Glioblastoma (GBM) is associated with infiltration of peritumoral (PT) parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the PT area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass (TM) is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in two-dimensional and three-dimensional migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation are required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators alpha V beta 3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, beta 3 integrin is upregulated in PT cells. Blockade of dimeric integrin alpha V beta 3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighboring tissue.

Original language	English
Article number	N/A
Pages (from-to)	1075-1085
Number of pages	11
Journal	Stem Cells
Volume	31
Issue number	6
DOIs	https://doi.org/10.1002/stem.1349
Publication status	Published - Jun 2013

Keywords

Glioblastoma-initiating cells
Invasion
Integrin alpha V beta 3
IN-VIVO
EXTRACELLULAR-MATRIX
GROWTH
ACTIVATION
MOTILITY
GLIOMA
EXPRESSION
INTEGRINS
PROTEIN
GTPASES

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Ruiz-Ontanon, P., Orgaz, J. L., Aldaz, B., Elosegui-Artola, A., Martino, J., Berciano, M. T., Montero, J. A., Grande, L., Nogueira, L., Diaz-Moralli, S., Esparis-Ogando, A., Vazquez-Barquero, A., Lafarga, M., Pandiella, A., Cascante, M., Segura, V., Martinez-Climent, J. A., Sanz Moreno, V., & Fernandez-Luna, J. L. (2013). Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of Glioblastoma-Initiating Cells that Infiltrate Peritumoral Tissue. Stem Cells, 31(6), 1075-1085. Article N/A. https://doi.org/10.1002/stem.1349

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title = "Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of Glioblastoma-Initiating Cells that Infiltrate Peritumoral Tissue",

abstract = "Glioblastoma (GBM) is associated with infiltration of peritumoral (PT) parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the PT area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass (TM) is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in two-dimensional and three-dimensional migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation are required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators alpha V beta 3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, beta 3 integrin is upregulated in PT cells. Blockade of dimeric integrin alpha V beta 3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighboring tissue.",

keywords = "Glioblastoma-initiating cells, Invasion, Integrin alpha V beta 3, IN-VIVO, EXTRACELLULAR-MATRIX, GROWTH, ACTIVATION, MOTILITY, GLIOMA, EXPRESSION, INTEGRINS, PROTEIN, GTPASES",

author = "Patricia Ruiz-Ontanon and Orgaz, {Jose L.} and Beatriz Aldaz and Alberto Elosegui-Artola and Juan Martino and Berciano, {Maria T.} and Montero, {Juan A.} and Lara Grande and Lorena Nogueira and Santiago Diaz-Moralli and Azucena Esparis-Ogando and Alfonso Vazquez-Barquero and Miguel Lafarga and Atanasio Pandiella and Marta Cascante and Victor Segura and Martinez-Climent, {Jose A.} and {Sanz Moreno}, Vicky and Fernandez-Luna, {Jose L.}",

year = "2013",

month = jun,

doi = "10.1002/stem.1349",

language = "English",

volume = "31",

pages = "1075--1085",

journal = "Stem Cells",

issn = "1066-5099",

publisher = "Nova Science Publishers Inc",

number = "6",

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Ruiz-Ontanon, P, Orgaz, JL, Aldaz, B, Elosegui-Artola, A, Martino, J, Berciano, MT, Montero, JA, Grande, L, Nogueira, L, Diaz-Moralli, S, Esparis-Ogando, A, Vazquez-Barquero, A, Lafarga, M, Pandiella, A, Cascante, M, Segura, V, Martinez-Climent, JA, Sanz Moreno, V & Fernandez-Luna, JL 2013, 'Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of Glioblastoma-Initiating Cells that Infiltrate Peritumoral Tissue', Stem Cells, vol. 31, no. 6, N/A, pp. 1075-1085. https://doi.org/10.1002/stem.1349

TY - JOUR

T1 - Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of Glioblastoma-Initiating Cells that Infiltrate Peritumoral Tissue

AU - Ruiz-Ontanon, Patricia

AU - Orgaz, Jose L.

AU - Aldaz, Beatriz

AU - Elosegui-Artola, Alberto

AU - Martino, Juan

AU - Berciano, Maria T.

AU - Montero, Juan A.

AU - Grande, Lara

AU - Nogueira, Lorena

AU - Diaz-Moralli, Santiago

AU - Esparis-Ogando, Azucena

AU - Vazquez-Barquero, Alfonso

AU - Lafarga, Miguel

AU - Pandiella, Atanasio

AU - Cascante, Marta

AU - Segura, Victor

AU - Martinez-Climent, Jose A.

AU - Sanz Moreno, Vicky

AU - Fernandez-Luna, Jose L.

PY - 2013/6

Y1 - 2013/6

N2 - Glioblastoma (GBM) is associated with infiltration of peritumoral (PT) parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the PT area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass (TM) is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in two-dimensional and three-dimensional migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation are required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators alpha V beta 3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, beta 3 integrin is upregulated in PT cells. Blockade of dimeric integrin alpha V beta 3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighboring tissue.

AB - Glioblastoma (GBM) is associated with infiltration of peritumoral (PT) parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the PT area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass (TM) is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in two-dimensional and three-dimensional migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation are required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators alpha V beta 3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, beta 3 integrin is upregulated in PT cells. Blockade of dimeric integrin alpha V beta 3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighboring tissue.

KW - Glioblastoma-initiating cells

KW - Invasion

KW - Integrin alpha V beta 3

KW - IN-VIVO

KW - EXTRACELLULAR-MATRIX

KW - GROWTH

KW - ACTIVATION

KW - MOTILITY

KW - GLIOMA

KW - EXPRESSION

KW - INTEGRINS

KW - PROTEIN

KW - GTPASES

U2 - 10.1002/stem.1349

DO - 10.1002/stem.1349

M3 - Article

SN - 1066-5099

VL - 31

SP - 1075

EP - 1085

JO - Stem Cells

JF - Stem Cells

IS - 6

M1 - N/A

ER -

Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of Glioblastoma-Initiating Cells that Infiltrate Peritumoral Tissue

Abstract

Keywords

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