Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Freeman, Spencer A.; McLeod, Sarah J.; Dukowski, Janet; Austin, Pamela; Lee, Crystal C.Y.; Millen-Martin, Brandie; Kubes, Paul; McCafferty, Donna–Marie; Gold, Michael R.; Roskelley, Calvin D.

doi:10.1158/0008-5472.can-09-3414

Cited by 41 publications

(40 citation statements)

References 39 publications

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“…Once adhered to LSECs, cancer cells must pass across the endothelium through a process called diapedesis in order to extravasate (76,77). The contraction of endothelial cells through actin cytoskeletal reorganization is essential for the infiltration of invading cells (78,79). The remodeling of the cytoskeleton is also observed after the binding of endothelial ICAM-1 to leukocyte LFA-1 during transmigration of immune cells, including leukocytes, lymphocytes and neutrophils (44,80,81).…”

Section: Tumor Cell Extravasation: Opening the Liver's Doors To Invadmentioning

confidence: 99%

Role of liver ICAM-1 in metastasis

2017

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Abstract. Intercellular adhesion molecule (ICAM)-1, is a transmembrane glycoprotein of the immunoglobulin (Ig)-like superfamily, consisting of five extracellular Ig-like domains, a transmembrane domain and a short cytoplasmic tail. ICAM-1 is expressed in various cell types, including endothelial cells and leukocytes, and is involved in several physiological processes. Furthermore, it has additionally been reported to be expressed in various cancer cells, including melanoma, colorectal cancer and lymphoma. The majority of studies to date have focused on the expression of the ICAM-1 on the surface of tumor cells, without research into ICAM-1 expression at sites of metastasis. Cancer cells frequently metastasize to the liver, due to its unique physiology and specialized liver sinusoid capillary network. Liver sinusoidal endothelial cells constitutively express ICAM-1, which is upregulated under inflammatory conditions. Furthermore, liver ICAM-1 may be important during the development of liver metastasis. Therefore, it is necessary to improve the understanding of the mechanisms mediated by this adhesion molecule in order to develop host-directed anticancer therapies.

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Section: Tumor Cell Extravasation: Opening the Liver's Doors To Invadmentioning

confidence: 99%

Role of liver ICAM-1 in metastasis

2017

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“…MDA-MB-231 cells transfected with miR-149 exhibited severely impaired spreading on collagen gels and haptotactic cell migration (116). The small GTPases Rap1a and Rap1b (118,119) as well as the G-protein coupled receptor interacting protein-1 (GIT-1) (120), an ADP-ribosylation factor GTPase activating protein (ArfGAP), were identified as direct targets of miR-149 (116,117). Inhibition of Rap1a and Rap1b by miR-149 results in aberrant src and RAC-1 activation, thereby promoting invasion (116).…”

Section: Breast Cancer Metastasis Suppressing Mirsmentioning

confidence: 99%

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

Weidle

Dickopf

Hintermair

et al. 2018

CGP

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“…To increase Rap1 activation in B16F1 melanoma cells, we expressed the constitutively active Rap1V12 protein (Freeman et al, 2010) and then compared focal adhesions in cells that were in relaxed versus uniaxially stretched 3D matrices. B16F1 cells stably expressing Rap1V12 formed vinculin-rich focal adhesions even in the absence of applied tension (Fig.…”

Section: Acute Stretch Activates Rap1 In Tumor Cellsmentioning

confidence: 99%

Applied stretch initiates directional invasion via the action of Rap1 GTPase as a tension sensor

Freeman

Christian

Austin

et al. 2016

Journal of Cell Science

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Although it is known that a stiffening of the stroma and the rearrangement of collagen fibers within the extracellular matrix facilitate the movement of tumor cells away from the primary lesion, the underlying mechanisms responsible are not fully understood. We now show that this invasion, which can be initiated by applying tensional loads to a three-dimensional collagen gel matrix in culture, is dependent on the Rap1 GTPases (Rap1a and Rap1b, referred to collectively as Rap1). Under these conditions Rap1 activity stimulates the formation of focal adhesion structures that align with the tensional axis as single tumor cells move into the matrix. These effects are mediated by the ability of Rap1 to induce the polarized polymerization and retrograde flow of actin, which stabilizes integrins and recruits vinculin to preformed adhesions, particularly those near the leading edge of invasive cells. Rap1 activity also contributes to the tensioninduced collective invasive elongation of tumor cell clusters and it enhances tumor cell growth in vivo. Thus, Rap1 mediates the effects of increased extracellular tension in multiple ways that are capable of contributing to tumor progression when dysregulated.

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Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Cited by 41 publications

References 39 publications

Role of liver ICAM-1 in metastasis

Role of liver ICAM-1 in metastasis

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

Applied stretch initiates directional invasion via the action of Rap1 GTPase as a tension sensor

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