title: Podocalyxin-like 1 promotes invadopodia formation and metastasis through activation of Rac1/Cdc42/cortactin signaling in breast cancer cells.
abstract: Metastatic disease is the leading cause of cancer mortality. Identifying biomarkers and regulatory mechanisms is important toward developing diagnostic and therapeutic tools against metastatic cancer. In this study, we demonstrated that podocalyxin-like 1 (PODXL) is overexpressed in breast tumor cells and increased in lymph node metastatic cancer. Mechanistically, we found that the expression of PODXL was associated with cell motility and invasiveness. Suppression of PODXL in MDA-MB-231 cells reduced lamellipodia formation and focal adhesion kinase (FAK) and paxillin phosphorylation. PODXL knockdown reduced the formation of invadopodia, such as inhibiting the colocalization of F-actin with cortactin and suppressing phosphorylation of cortactin and neural Wiskott-Aldrich syndrome protein. Conversely, overexpression of PODXL in MCF7 cells induced F-actin/cortactin colocalization and enhanced invadopodia formation and activation. Invadopodia activity and tumor invasion in PODXL-knockdown cells are similar to that in cortactin-knockdown cells. We further found that the DTHL motif in PODXL is crucial for regulating cortactin phosphorylation and Rac1/Cdc42 activation. Inhibition of Rac1/Cdc42 impeded PODXL-mediated cortactin activation and FAK and paxillin phosphorylation. Moreover, inhibition of PODXL in MDA-MB-231 cells significantly suppressed tumor colonization in the lungs and distant metastases, similar to those in cortactin-knockdown cells. These findings show that overexpression of PODXL enhanced invadopodia formation and tumor metastasis by inducing Rac1/Cdc42/cortactin signaling network.
authors: Department of Biochemistry, School of Medicine, Taipei Medical University, Taipei 110, Taiwan, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, hcw0928@gate.sinica.edu.tw cwlin@tmu.edu.tw.
authors: Cheng-Wei
authors: CW
authors: Lin
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, Graduate Institute of Oral Biology, School of Dentistry, College of Medicine, National Taiwan University, Taipei 106, Taiwan and.
authors: Min-Siou
authors: MS
authors: Sun
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
authors: Mei-Ying
authors: MY
authors: Liao
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
authors: Chu-Hung
authors: CH
authors: Chung
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
authors: Yi-Hsuan
authors: YH
authors: Chi
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
authors: Li-Tin
authors: LT
authors: Chiou
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors: John
authors: J
authors: Yu
authors: Graduate Institute of Oral Biology, School of Dentistry, College of Medicine, National Taiwan University, Taipei 106, Taiwan and.
authors: Kuo-Lung
authors: KL
authors: Lou
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, Graduate Institute of Oral Biology, School of Dentistry, College of Medicine, National Taiwan University, Taipei 106, Taiwan and Genomics Research Center, Academia Sinica, Taipei 115, Taiwan cwlin@tmu.edu.tw.
authors: Han-Chung
authors: HC
authors: Wu
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D051356:Cortactin / Q000096:biosynthesis* / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D011554:Pseudopodia / Q000235:genetics; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051356:Cortactin; C107953:RAC1 protein, human; D012795:Sialoglycoproteins; C001643:podocalyxin; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein