PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion

Gont, Alexander; Daneshmand, Manijeh; Woulfe, John; Lorimer, Ian A. J.

doi:10.1016/s0959-8049(16)61607-6

Cited by 8 publications

(16 citation statements)

References 17 publications

(23 reference statements)

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“…The contribution of PREX1 to tumor cell proliferation also remains controversial. Several groups have shown that PREX1 does not affect in vitro proliferation or activation of ERK signaling in breast [37], melanoma [38], or glioblastoma cancer cells [39]. However, others implicate PREX1 in activating IGF-1R/InsR [15], PI3K/AKT [17], and MEK/ERK [17,18] signaling following growth factor stimulation in vitro and that this signaling activation promotes primary tumor growth in vivo [16,17].…”

Section: Discussionmentioning

confidence: 99%

PREX1 drives spontaneous bone dissemination of ER+ breast cancer cells

Clements

Johnson

2019

Oncogene

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A significant proportion of breast cancer patients develop bone metastases, but the mechanisms regulating tumor cell dissemination from the primary site to the skeleton remain largely unknown. Using a novel model of spontaneous bone metastasis derived from human ER+ MCF7 cells, molecular profiling revealed increased PREX1 expression in a cell line established from bonedisseminated MCF7 cells (MCF7b), which were more migratory, invasive, and adhesive in vitro compared to parental MCF7 cells, and this phenotype was mediated by PREX1. MCF7b cells grew poorly in the primary tumor site when re-inoculated in vivo, suggesting these cells are primed to grow in the bone, and were enriched in skeletal sites of metastasis over soft tissue sites. Skeletal dissemination from the primary tumor was reversed with PREX1 knockdown, indicating that PREX1 is a key driver of spontaneous dissemination of tumor cells from the primary site to the bone marrow. In breast cancer patients, PREX1 levels are significantly increased in ER+ tumors and associated with invasive disease and distant metastasis. Together, these findings implicate PREX1 in spontaneous bone dissemination and provide a significant advance to the molecular mechanisms by which breast cancer cells disseminate from the primary tumor site to bone.

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Section: Discussionmentioning

confidence: 99%

PREX1 drives spontaneous bone dissemination of ER+ breast cancer cells

Clements

Johnson

2019

Oncogene

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“…Additionally, DOCK 7 is reported to play a critical role in the invasive behavior of the glioblastoma and mediates Rac1 activation following HGF stimulation [90]. Another Rac GEF that promotes Rac1-mediated invasion in glioblastoma cells is PREX1, which is overexpressed in GBM and responds to the presence of the upregulated Pi3K pathway [91].…”

Section: Upstream Regulatorsmentioning

confidence: 99%

The Role of Rho GTPases in Motility and Invasion of Glioblastoma Cells

Al-Koussa

Atat

Jaafar

et al. 2020

Analytical Cellular Pathology

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Astrocytomas are primary malignant brain tumors that originate from astrocytes. Grade IV astrocytoma or glioblastoma is a highly invasive tumor that occur within the brain parenchyma. The Rho family of small GTPases, which includes Rac1, Cdc42, and RhoA, is an important family whose members are key regulators of the invasion and migration of glioblastoma cells. In this review, we describe the role played by the Rho family of GTPases in the regulation of the invasion and migration of glioblastoma cells. Specifically, we focus on the role played by RhoA, Rac1, RhoG, and Cdc42 in cell migration through rearrangement of actin cytoskeleton, cell adhesion, and invasion. Finally, we highlight the importance of potentially targeting Rho GTPases in the treatment of glioblastoma.

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“…4), has been pointed as a target for glioma treatment, by promoting glioma cell proliferation via the TLR4/NF-κB signaling pathway [28]. PREX1 and ABHD2 have also shown to promote tumor invasion and progression in glioblastoma [29,30], while the tumor sup-pressor BIN1 was found to be regulated by HNRNPA2B1, a putative proto-oncogene in GBM [31].…”

Section: Discussionmentioning

confidence: 99%

Tracking intratumoral heterogeneity in glioblastoma via regularized classification of single-cell RNA-Seq data

Lopes

Vinga

2020

BMC Bioinformatics

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Background: Understanding cellular and molecular heterogeneity in glioblastoma (GBM), the most common and aggressive primary brain malignancy, is a crucial step towards the development of effective therapies. Besides the inter-patient variability, the presence of multiple cell populations within tumors calls for the need to develop modeling strategies able to extract the molecular signatures driving tumor evolution and treatment failure. With the advances in single-cell RNA Sequencing (scRNA-Seq), tumors can now be dissected at the cell level, unveiling information from their life history to their clinical implications. Results: We propose a classification setting based on GBM scRNA-Seq data, through sparse logistic regression, where different cell populations (neoplastic and normal cells) are taken as classes. The goal is to identify gene features discriminating between the classes, but also those shared by different neoplastic clones. The latter will be approached via the network-based twiner regularizer to identify gene signatures shared by neoplastic cells from the tumor core and infiltrating neoplastic cells originated from the tumor periphery, as putative disease biomarkers to target multiple neoplastic clones. Our analysis is supported by the literature through the identification of several known molecular players in GBM. Moreover, the relevance of the selected genes was confirmed by their significance in the survival outcomes in bulk GBM RNA-Seq data, as well as their association with several Gene Ontology (GO) biological process terms. Conclusions:We presented a methodology intended to identify genes discriminating between GBM clones, but also those playing a similar role in different GBM neoplastic clones (including migrating cells), therefore potential targets for therapy research. Our results contribute to a deeper understanding on the genetic features behind GBM, by disclosing novel therapeutic directions accounting for GBM heterogeneity.

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PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion

Cited by 8 publications

References 17 publications

PREX1 drives spontaneous bone dissemination of ER+ breast cancer cells

PREX1 drives spontaneous bone dissemination of ER+ breast cancer cells

The Role of Rho GTPases in Motility and Invasion of Glioblastoma Cells

Tracking intratumoral heterogeneity in glioblastoma via regularized classification of single-cell RNA-Seq data

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