RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription

Gerald, Damien; Adini, Irit; Shechter, Sharon; Perruzzi, Carole; Varnau, J.; Hopkins, Benjamin D.; Kazerounian, Shiva; Kurschat, Peter; Blachon, Stéphanie; Khedkar, Santosh A.; Bagchi, Mandrita; Sherris, David; Prendergast, George C.; Klagsbrun, Michael; Stuhlmann, Heidi; Rigby, Alan C.; Nagy, Janice A.; Benjamin, Laura E.

doi:10.1038/ncomms3824

Cited by 54 publications

(58 citation statements)

References 51 publications

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“…Notably, it was reported that RhoB has a critical role in angiogenesis and controls stromal endothelial cells during breast tumorigenesis. 23,39 Among the transcriptional factors involved in mesenchymal migration, we observed that Slug, one of the most thoroughly investigated EMT regulators in lung cancer, 40 was strongly induced following RhoB loss. In parallel, E-cadherin, epithelial marker of EMT known to be downregulated notably by Slug, showed reduced levels of mRNA and protein.…”

Section: Discussionmentioning

confidence: 96%

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

et al. 2015

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Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, which is mainly due to its high risk of metastatic dissemination. One critical point of this process is the ability of cancer cells to detach from the primary tumor and migrate through the extracellular matrix; however, the underlying molecular mechanisms are not yet fully understood. In the present study, we identified the small GTPase RhoB as a key regulator of bronchial cell morphology in a three-dimensional (3D) matrix. RhoB loss, which is frequently observed during lung cancer progression, induced an epithelial-mesenchymal transition (EMT) characterized by an increased proportion of invasive elongated cells in 3D. The process was mediated by Slug induction and E-cadherin repression. In addition, downregulation of RhoB induced Akt1 activation, which in turn activated Rac1 through the guanine-exchange factor Trio to control cell shape rearrangement. Further, we provide evidence that RhoB interacted with and positively regulates phosphatase PP2A through the recruitment of its regulatory subunit B55, which was found to be crucial for Akt dephosphorylation. B55 inhibition completely suppressed RhoB-mediated PP2A regulation. Finally, we show that PP2A inactivation, by targeting either its catalytic or its regulatory B55 subunit, completely reversed RhoB-dependent morphological changes and also fully prevented the ability of RhoB to decrease the invasiveness of bronchial cells. Altogether, these results highlight a novel signaling axis and describe new molecular mechanisms that could explain the tumor suppressor role of RhoB in lung cancer. Therefore, we propose that RhoB could be responsible for early metastatic prevention by inhibiting the EMT-derived invasiveness of lung cells through the control of PP2A activity.

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Section: Discussionmentioning

confidence: 96%

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

et al. 2015

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“…These distinct posttranslational modifications affect RhoB localization and function . In contrast to RhoA and RhoC, RhoB is localized not only at the plasma membrane but also in endosomes, multivesicular bodies, and has even been reported in the nucleus . Unlike most small GTPases, which are relatively stable, RhoB has a high rate of turnover at the protein level.…”

Section: Introductionmentioning

confidence: 99%

“…5 In contrast to RhoA and RhoC, RhoB is localized not only at the plasma membrane but also in endosomes, multivesicular bodies, and has even been reported in the nucleus. [6][7][8] Unlike most small GTPases, which are relatively stable, RhoB has a high rate of turnover at the protein level. Its synthesis is rapidly upregulated by many stimuli, including cellular stress, growth factors, and cytokines, which ultimately helps RhoB regulate many cellular responses like proliferation, survival, and apoptosis.…”

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confidence: 99%

RhoB is regulated by hypoxia and modulates metastasis in breast cancer

Godet

DiGiacomo

et al. 2019

Cancer Reports

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Background RhoB is a Rho family GTPase that is highly homologous to RhoA and RhoC. RhoA and RhoC have been shown to promote tumor progression in many cancer types; however, a distinct role for RhoB in cancer has not been delineated. Additionally, several well‐characterized studies have shown that small GTPases such as RhoA, Rac1, and Cdc42 are induced in vitro under hypoxia, but whether and how hypoxia regulates RhoB in breast cancer remains elusive. Aims To determine whether and how hypoxia regulates RhoB expression and to understand the role of RhoB in breast cancer metastasis. Methods We investigated the effects of hypoxia on the expression and activation of RhoB using real‐time quantitative polymerase chain reaction and western blotting. We also examined the significance of both decreased and increased RhoB expression in breast cancer using CRISPR depletion of RhoB or a vector overexpressing RhoB in 3D in vitro migration models and in an in vivo mouse model. Results We found that hypoxia significantly upregulated RhoB mRNA and protein expression resulting in increased levels of activated RhoB. Both loss of RhoB and gain of RhoB expression led to reduced migration in a 3D collagen matrix and invasion within a multicellular 3D spheroid. We showed that neither the reduction nor overexpression of RhoB affected tumor growth in vivo. While the loss of RhoB had no effect on metastasis, RhoB overexpression led to decreased metastasis to the lungs, liver, and lymph nodes of mice. Conclusion Our results suggest that RhoB may have an important role in suppressing breast cancer metastasis.

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“…Also, human clinical samples of ATC with BRAF V600E compared to BRAF WT -ATC tend to recruit blood microvascular endothelial cells in the intratumoral area, suggesting that increased ATC-associated angiogenesis might play a role to supply energy/nutrients and support intravascular invasion and ultimately metastasis. It is widely known that VEGFA and VEGFC are potent angiogenic and lymphangiogenic factors [52], respectively, which regulate blood and lymphatic vessels endothelial cell migration and proliferation through the VEGFR2 (vascular endothelial growth factor receptor 2) intracellular signaling cascade [28]. VEGFA [53] and VEGFC [51] have been reported to be highly expressed in PTC over normal thyroid tissue or benign lesions and correlate with increased angiogenesis and lymphatic vessel density [51; 53; 54; 55].…”

Section: Discussionmentioning

confidence: 99%

“…Human thyroid cancer cells were grown in DMEM high glucose (CellGro, USA) medium supplemented with 10% fetal bovine serum (FBS) (CellGro, USA) and ampicillin/streptomycin. Primary human microvascular endothelial cells (blood vessel endothelial cells (BVECs) and lymphatic vessel endothelial cells (LVECs)) [28] were kindly provided from Dr. Harold F. Dvorak (BIDMC, Harvard Medical School, Boston, USA). BVECs and LVECs were grown in MCDB 131 (Life Technologies, USA) growth medium with additional glutgro (Corning, final concentration 2 mM) and MVGS (microvascular growth supplement) (Life Technologies, USA).…”

Section: Methodsmentioning

confidence: 99%

Expression of angiogenic switch, cachexia and inflammation factors at the crossroad in undifferentiated thyroid carcinoma with BRAF

Husain

Sadow

et al. 2016

Cancer Letters

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Cachexia is the result of complex metabolic alterations which causes morbidity in patients with advanced cancers including undifferentiated (anaplastic) thyroid carcinoma (ATC). ATC is a lethal disease with limited therapeutic options and unclear etiology for cachexia. We hypothesize that the BRAFV600E oncoprotein triggers microvascular endothelial cell tubule formation (in vitro angiogenesis) by means of factors which play a crucial role in angiogenic switch, inflammation/immune response and cachexia. We use human ATC cells and applied multiplex ELISA assay to screen for and measure angiogenic/cachectic and pro-inflammatory factors in the ATC-derived secretome. We find that vemurafenib anti-BRAFV600E therapy significantly reduces secreted VEGFA, VEGFC and IL6 protein levels compared to vehicle-treated ATC cells. As a result, the secretome from vemurafenib-treated ATC cells inhibits microvascular endothelial cell-related in vitro angiogenesis. Furthermore, ATC clinical samples express VEGFA, VEGFC and IL6 proteins. Our results suggest that angiogenic/cachectic and pro-inflammatory/immune response factors could play a crucial role in BRAFV600E-positive human ATC aggressiveness. Understanding the extent to which microenvironment-associated angiogenic factors participate in cachexia and cancer metabolism in advanced thyroid cancers will reveal new biomarkers and foster novel therapeutic approaches.

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RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription

Cited by 54 publications

References 51 publications

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

RhoB is regulated by hypoxia and modulates metastasis in breast cancer

Expression of angiogenic switch, cachexia and inflammation factors at the crossroad in undifferentiated thyroid carcinoma with BRAF

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