Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma

Tracy A. Marko, Ghaidan A Shamsan, Elizabeth N. Edwards, Paige E. Hazelton, Sue Rathe, Ingrid Cornax, Paula R. Overn, Jyotika Varshney, Brandon J. Diessner, Branden S Moriarity, Gerard O'Sullivan, David J Odde, David A Largaespada

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2. Proliferation, migration, and anchorage independent growth were evaluated. RNA sequencing and immunohistochemistry of human osteosarcoma tissue samples were used to further evaluate the potential role of the Slit-Robo pathway in osteosarcoma. The effects of Srgap2 expression modulation in the murine OS cell lines support the hypothesis that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. Additionally, SRGAP2 and other genes in the Slit-Robo pathway have altered transcript levels in a subset of mouse and human osteosarcoma, and SRGAP2 protein expression is reduced or absent in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in osteosarcoma metastasis, with loss of SRGAP2 potentially contributing to a more aggressive phenotype.

Original languageEnglish (US)
Article number39059
JournalScientific reports
Volume6
DOIs
StatePublished - Dec 14 2016

Fingerprint

GTPase-Activating Proteins
Osteosarcoma
Neoplasm Metastasis
Cell Line
Clustered Regularly Interspaced Short Palindromic Repeats
RNA Sequence Analysis
Beauty
Treatment Failure
Mutagenesis
Neoplasms
Immunohistochemistry
Phenotype
Bone and Bones

Cite this

Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma. / Marko, Tracy A.; Shamsan, Ghaidan A; Edwards, Elizabeth N.; Hazelton, Paige E.; Rathe, Sue; Cornax, Ingrid; Overn, Paula R.; Varshney, Jyotika; Diessner, Brandon J.; Moriarity, Branden S; O'Sullivan, Gerard; Odde, David J; Largaespada, David A.

In: Scientific reports, Vol. 6, 39059, 14.12.2016.

Research output: Contribution to journalArticle

Marko, TA, Shamsan, GA, Edwards, EN, Hazelton, PE, Rathe, S, Cornax, I, Overn, PR, Varshney, J, Diessner, BJ, Moriarity, BS, O'Sullivan, G, Odde, DJ & Largaespada, DA 2016, 'Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma', Scientific reports, vol. 6, 39059. https://doi.org/10.1038/srep39059
Marko, Tracy A. ; Shamsan, Ghaidan A ; Edwards, Elizabeth N. ; Hazelton, Paige E. ; Rathe, Sue ; Cornax, Ingrid ; Overn, Paula R. ; Varshney, Jyotika ; Diessner, Brandon J. ; Moriarity, Branden S ; O'Sullivan, Gerard ; Odde, David J ; Largaespada, David A. / Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma. In: Scientific reports. 2016 ; Vol. 6.
@article{6571d3c9ecef4439b6648a0707af5528,
title = "Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma",
abstract = "Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2. Proliferation, migration, and anchorage independent growth were evaluated. RNA sequencing and immunohistochemistry of human osteosarcoma tissue samples were used to further evaluate the potential role of the Slit-Robo pathway in osteosarcoma. The effects of Srgap2 expression modulation in the murine OS cell lines support the hypothesis that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. Additionally, SRGAP2 and other genes in the Slit-Robo pathway have altered transcript levels in a subset of mouse and human osteosarcoma, and SRGAP2 protein expression is reduced or absent in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in osteosarcoma metastasis, with loss of SRGAP2 potentially contributing to a more aggressive phenotype.",
author = "Marko, {Tracy A.} and Shamsan, {Ghaidan A} and Edwards, {Elizabeth N.} and Hazelton, {Paige E.} and Sue Rathe and Ingrid Cornax and Overn, {Paula R.} and Jyotika Varshney and Diessner, {Brandon J.} and Moriarity, {Branden S} and Gerard O'Sullivan and Odde, {David J} and Largaespada, {David A}",
year = "2016",
month = "12",
day = "14",
doi = "10.1038/srep39059",
language = "English (US)",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma

AU - Marko, Tracy A.

AU - Shamsan, Ghaidan A

AU - Edwards, Elizabeth N.

AU - Hazelton, Paige E.

AU - Rathe, Sue

AU - Cornax, Ingrid

AU - Overn, Paula R.

AU - Varshney, Jyotika

AU - Diessner, Brandon J.

AU - Moriarity, Branden S

AU - O'Sullivan, Gerard

AU - Odde, David J

AU - Largaespada, David A

PY - 2016/12/14

Y1 - 2016/12/14

N2 - Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2. Proliferation, migration, and anchorage independent growth were evaluated. RNA sequencing and immunohistochemistry of human osteosarcoma tissue samples were used to further evaluate the potential role of the Slit-Robo pathway in osteosarcoma. The effects of Srgap2 expression modulation in the murine OS cell lines support the hypothesis that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. Additionally, SRGAP2 and other genes in the Slit-Robo pathway have altered transcript levels in a subset of mouse and human osteosarcoma, and SRGAP2 protein expression is reduced or absent in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in osteosarcoma metastasis, with loss of SRGAP2 potentially contributing to a more aggressive phenotype.

AB - Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2. Proliferation, migration, and anchorage independent growth were evaluated. RNA sequencing and immunohistochemistry of human osteosarcoma tissue samples were used to further evaluate the potential role of the Slit-Robo pathway in osteosarcoma. The effects of Srgap2 expression modulation in the murine OS cell lines support the hypothesis that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. Additionally, SRGAP2 and other genes in the Slit-Robo pathway have altered transcript levels in a subset of mouse and human osteosarcoma, and SRGAP2 protein expression is reduced or absent in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in osteosarcoma metastasis, with loss of SRGAP2 potentially contributing to a more aggressive phenotype.

UR - http://www.scopus.com/inward/record.url?scp=85006152617&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006152617&partnerID=8YFLogxK

U2 - 10.1038/srep39059

DO - 10.1038/srep39059

M3 - Article

C2 - 27966608

AN - SCOPUS:85006152617

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 39059

ER -