TY - JOUR
T1 - The role of Tks adaptor proteins in invadopodia formation, growth and metastasis of melanoma
AU - Iizuka, Shinji
AU - Abdullah, Christopher
AU - Buschman, Matthew D.
AU - Diaz, Begoña
AU - Courtneidge, Sara A.
N1 - Funding Information:
This work was supported by grants from the R01 CA129686 and R01 CA154002 from the NCI to SAC, and F31 CA180740 from the NCI to CA. We thank the personnel in the Histology, Animal and Lentivirus Production Cores at Sanford|Burnham|Prebys Medical Discovery Institute for technical assistance, the Lentiviral Service at OHSU for lentivirus production, Dr. Stefanie Kaech Petrie in the OHSU Advanced Microscopy Core for assistance with imaging, Dr. Lisa Coussens for the use of her slide scanner, Dr. Philippe Chavrier for the pHluorin-MT1-MMP construct. We thank Dr. Christine Gould for her involvement in the earlier stages of this work, and all members of the Courtneidge laboratory for discussion and input. We also thank Steven Marroulis at the Cancer Diagnosis Program (CDP) of National Cancer Institute for providing tissue microarray samples and information.
PY - 2016
Y1 - 2016
N2 - Metastatic cancer cells are characterized by their ability to degrade and invade through extracellular matrix. We previously showed that the Tks adaptor proteins, Tks4 and Tks5, are required for invadopodia formation and/or function in Srctransformed fibroblasts and a number of human cancer cell types. In this study, we investigated the role of Tks adaptor proteins in melanoma cell invasion and metastasis. Knockdown of either Tks4 or Tks5 in both mouse and human melanoma cell lines resulted in a decreased ability to form invadopodia and degrade extracellular matrix. In addition, Tks-knockdown melanoma cells had decreased proliferation in a 3-dimensional type l collagen matrix, but not in 2-dimensional culture conditions. We also investigated the role of Tks proteins in melanoma progression in vivo using xenografts and experimental metastasis assays. Consistent with our in vitro results, reduction of Tks proteins markedly reduced subcutaneous melanoma growth as well as metastatic growth in the lung. We explored the clinical relevance of Tks protein expression in human melanoma specimens using a tissue microarray. Compared to non-malignant nevi, both Tks proteins were highly expressed in melanoma tissues. Moreover, metastatic melanoma cases showed higher expression of Tks5 than primary melanoma cases. Taken together, these findings suggest the importance of Tks adaptor proteins in melanoma growth and metastasis in vivo, likely via functional invadopodia formation.
AB - Metastatic cancer cells are characterized by their ability to degrade and invade through extracellular matrix. We previously showed that the Tks adaptor proteins, Tks4 and Tks5, are required for invadopodia formation and/or function in Srctransformed fibroblasts and a number of human cancer cell types. In this study, we investigated the role of Tks adaptor proteins in melanoma cell invasion and metastasis. Knockdown of either Tks4 or Tks5 in both mouse and human melanoma cell lines resulted in a decreased ability to form invadopodia and degrade extracellular matrix. In addition, Tks-knockdown melanoma cells had decreased proliferation in a 3-dimensional type l collagen matrix, but not in 2-dimensional culture conditions. We also investigated the role of Tks proteins in melanoma progression in vivo using xenografts and experimental metastasis assays. Consistent with our in vitro results, reduction of Tks proteins markedly reduced subcutaneous melanoma growth as well as metastatic growth in the lung. We explored the clinical relevance of Tks protein expression in human melanoma specimens using a tissue microarray. Compared to non-malignant nevi, both Tks proteins were highly expressed in melanoma tissues. Moreover, metastatic melanoma cases showed higher expression of Tks5 than primary melanoma cases. Taken together, these findings suggest the importance of Tks adaptor proteins in melanoma growth and metastasis in vivo, likely via functional invadopodia formation.
KW - Invadopodia
KW - MT1-MMP
KW - Melanoma
KW - Tks4
KW - Tks5
UR - http://www.scopus.com/inward/record.url?scp=84998962538&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84998962538&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.12954
DO - 10.18632/oncotarget.12954
M3 - Article
C2 - 27802184
AN - SCOPUS:84998962538
SN - 1949-2553
VL - 7
SP - 78473
EP - 78486
JO - Oncotarget
JF - Oncotarget
IS - 48
ER -