ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma
Metastases are the primary cause of cancer-related deaths. The underlying molecular and biological mechanisms remain, however, elusive, thus preventing the design of specific therapies. In melanomas, the metastatic process is influenced by the acquisition of metastasis-associated mutational and epig...
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doaj-ab6c40d547fc485b886e220251986af32020-11-25T04:06:04ZengMDPI AGCancers2072-66942020-11-01123366336610.3390/cancers12113366ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in MelanomaEwa Aladowicz0Letizia Granieri1Federica Marocchi2Simona Punzi3Giuseppina Giardina4Pier Francesco Ferrucci5Giovanni Mazzarol6Maria Capra7Giuseppe Viale8Stefano Confalonieri9Sara Gandini10Fiorenza Lotti11Luisa Lanfrancone12Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research (ICR), 15 Cotswold Road, Sutton SM2 5NG, UKDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO), Via Adamello, 16, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO), Via Adamello, 16, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO), Via Adamello, 16, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO), Via Adamello, 16, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO), Via Adamello, 16, 20139 Milan, ItalyDivision of Pathology, European Institute of Oncology IRCCS (IEO), Via Ripamonti 435, 20141 Milan, ItalyDivision of Pathology, European Institute of Oncology IRCCS (IEO), Via Ripamonti 435, 20141 Milan, ItalyDivision of Pathology, European Institute of Oncology IRCCS (IEO), Via Ripamonti 435, 20141 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO), Via Adamello, 16, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO), Via Adamello, 16, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO), Via Adamello, 16, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO), Via Adamello, 16, 20139 Milan, ItalyMetastases are the primary cause of cancer-related deaths. The underlying molecular and biological mechanisms remain, however, elusive, thus preventing the design of specific therapies. In melanomas, the metastatic process is influenced by the acquisition of metastasis-associated mutational and epigenetic traits and the activation of metastatic-specific signaling pathways in the primary melanoma. In the current study, we investigated the role of an adaptor protein of the Shc family (ShcD) in the acquisition of metastatic properties by melanoma cells, exploiting our cohort of patient-derived xenografts (PDXs). We provide evidence that the depletion of ShcD expression increases a spread cell shape and the capability of melanoma cells to attach to the extracellular matrix while its overexpression switches their morphology from elongated to rounded on 3D matrices, enhances cells’ invasive phenotype, as observed on collagen gel, and favors metastasis formation in vivo. ShcD overexpression sustains amoeboid movement in melanoma cells, by suppressing the Rac1 signaling pathway through the confinement of DOCK4 in the cytoplasm. Inactivation of the ShcD signaling pathway makes melanoma cells more sensitive to therapeutic treatments. Consistently, ShcD expression predicts poor outcome in a cohort of 183 primary melanoma patients.https://www.mdpi.com/2072-6694/12/11/3366melanoma metastasisShcD adaptor proteinamoeboid motilityRac1DOCK4melanoma PDX |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ewa Aladowicz Letizia Granieri Federica Marocchi Simona Punzi Giuseppina Giardina Pier Francesco Ferrucci Giovanni Mazzarol Maria Capra Giuseppe Viale Stefano Confalonieri Sara Gandini Fiorenza Lotti Luisa Lanfrancone |
spellingShingle |
Ewa Aladowicz Letizia Granieri Federica Marocchi Simona Punzi Giuseppina Giardina Pier Francesco Ferrucci Giovanni Mazzarol Maria Capra Giuseppe Viale Stefano Confalonieri Sara Gandini Fiorenza Lotti Luisa Lanfrancone ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma Cancers melanoma metastasis ShcD adaptor protein amoeboid motility Rac1 DOCK4 melanoma PDX |
author_facet |
Ewa Aladowicz Letizia Granieri Federica Marocchi Simona Punzi Giuseppina Giardina Pier Francesco Ferrucci Giovanni Mazzarol Maria Capra Giuseppe Viale Stefano Confalonieri Sara Gandini Fiorenza Lotti Luisa Lanfrancone |
author_sort |
Ewa Aladowicz |
title |
ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma |
title_short |
ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma |
title_full |
ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma |
title_fullStr |
ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma |
title_full_unstemmed |
ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma |
title_sort |
shcd binds dock4, promotes ameboid motility and metastasis dissemination, predicting poor prognosis in melanoma |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-11-01 |
description |
Metastases are the primary cause of cancer-related deaths. The underlying molecular and biological mechanisms remain, however, elusive, thus preventing the design of specific therapies. In melanomas, the metastatic process is influenced by the acquisition of metastasis-associated mutational and epigenetic traits and the activation of metastatic-specific signaling pathways in the primary melanoma. In the current study, we investigated the role of an adaptor protein of the Shc family (ShcD) in the acquisition of metastatic properties by melanoma cells, exploiting our cohort of patient-derived xenografts (PDXs). We provide evidence that the depletion of ShcD expression increases a spread cell shape and the capability of melanoma cells to attach to the extracellular matrix while its overexpression switches their morphology from elongated to rounded on 3D matrices, enhances cells’ invasive phenotype, as observed on collagen gel, and favors metastasis formation in vivo. ShcD overexpression sustains amoeboid movement in melanoma cells, by suppressing the Rac1 signaling pathway through the confinement of DOCK4 in the cytoplasm. Inactivation of the ShcD signaling pathway makes melanoma cells more sensitive to therapeutic treatments. Consistently, ShcD expression predicts poor outcome in a cohort of 183 primary melanoma patients. |
topic |
melanoma metastasis ShcD adaptor protein amoeboid motility Rac1 DOCK4 melanoma PDX |
url |
https://www.mdpi.com/2072-6694/12/11/3366 |
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