title: The CD44s splice isoform is a central mediator for invadopodia activity.
abstract: The ability for tumor cells to spread and metastasize to distant organs requires proteolytic degradation of extracellular matrix (ECM). This activity is mediated by invadopodia, actin-rich membrane protrusions that are enriched for proteases. However, the mechanisms underlying invadopodia activity are not fully understood. Here, we report that a specific CD44 splice isoform, CD44s, is an integral component in invadopodia. We show that CD44s, but not another splice isoform CD44v, is localized in invadopodia. Small hairpin (sh)RNA-mediated depletion of CD44s abolishes invadopodia activity, prevents matrix degradation and decreases tumor cell invasiveness. Our results suggest that CD44s promotes cortactin phosphorylation and recruits MT1-MMP (also known as MMP14) to sites of matrix degradation, which are important activities for invadopodia function. Importantly, we show that depletion of CD44s inhibits breast cancer cell metastasis to the lung in animals. These findings suggest a crucial mechanism underlying the role of the CD44s splice isoform in breast cancer metastasis.
authors: Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Pu
authors: P
authors: Zhao
authors: Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Yilin
authors: Y
authors: Xu
authors: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors: Yong
authors: Y
authors: Wei
authors: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors: Qiong
authors: Q
authors: Qiu
authors: Cell Imaging Facility & Nikon Imaging Center, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Teng-Leong
authors: TL
authors: Chew
authors: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors: Yibin
authors: Y
authors: Kang
authors: Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA chengc@northwestern.edu.
authors: Chonghui
authors: C
authors: Cheng
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D051356:Cortactin / Q000378:metabolism; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary*; D061986:MCF-7 Cells; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000235:genetics; D000069261:Podosomes / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: C497483:CD44 protein, human; D051356:Cortactin; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D053511:Matrix Metalloproteinase 14
keywords: Breast cancer; CD44s; Invadopodia; Metastasis; Splice isoform