title: p70 S6 kinase drives ovarian cancer metastasis through multicellular spheroid-peritoneum interaction and P-cadherin/b1 integrin signaling activation.
abstract: Peritoneal dissemination as a manifestation of ovarian cancer is an adverse prognostic factor associated with poor clinical outcome, and is thus a potentially promising target for improved treatment. Sphere forming cells (multicellular spheroids) present in malignant ascites of patients with ovarian cancer represent a major impediment to effective treatment. p70 S6 kinase (p70S6K), which is a downstream effector of mammalian target of rapamycin, is frequently hyperactivated in human ovarian cancer. Here, we identified p70S6K as an important regulator for the seeding and successful colonization of ovarian cancer spheroids on the peritoneum. Furthermore, we provided evidence for the existence of a novel crosstalk between P-cadherin and β1 integrin, which was crucial for the high degree of specificity in cell adhesion. In particular, we demonstrated that the upregulation of mature β1 integrin occurred as a consequence of P-cadherin expression through the induction of the Golgi glycosyltransferase, ST6Gal-I, which mediated β1 integrin hypersialylation. Loss of p70S6K or targeting the P-cadherin/β1-integrin interplay could significantly attenuate the metastatic spread onto the peritoneum in vivo. These findings establish a new role for p70S6K in tumor spheroid-mesothelium communication in ovarian cancer and provide a preclinical rationale for targeting p70S6K as a new avenue for microenvironment-based therapeutic strategy.
authors.affiliation: School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong.
authors.forename: Carman Ka Man
authors.initials: CK
authors.lastname: Ip
authors.affiliation: Department of Medicine, University of Hong Kong, Sassoon Road, Hong Kong.
authors.forename: Susan
authors.initials: S
authors.lastname: Yung
authors.affiliation: Department of Medicine, University of Hong Kong, Sassoon Road, Hong Kong.
authors.forename: Tak-Mao
authors.initials: TM
authors.lastname: Chan
authors.affiliation: Department of Anatomy, University of Hong Kong, Sassoon Road, Hong Kong.
authors.forename: Sai-Wah
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong.
authors.forename: Alice Sze Tsai
authors.initials: AS
authors.lastname: Wong
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000096:biosynthesis / Q000378:metabolism; D051177:Catenins / Q000235:genetics; D002448:Cell Adhesion; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D010537:Peritoneum / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000095002:Delta Catenin; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051177:Catenins; D019012:Integrin beta1; D034741:RNA, Small Interfering; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D012799:Sialyltransferases; D000095002:Delta Catenin; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase