p70 S6 kinase drives ovarian cancer metastasis through multicellular spheroid-peritoneum interaction and P-cadherin/β1 integrin signaling activation

// Carman Ka Man Ip 1 , Susan Yung 2 , Tak-Mao Chan 2 , Sai-Wah Tsao 3 , Alice Sze Tsai Wong 1 1 School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong 2 Department of Medicine, University of Hong Kong, Sassoon Road, Hong Kong 3 Department of Anatomy, University of Hong Kong, Sassoon Road, Hong Kong Correspondence to: Dr. Alice Sze Tsai Wong, email: awong1@hku.hk Keywords: p70 S6K , P-cadherin, β1 integrin, adhesion, metastasis Received: May 21, 2014      Accepted: August 18, 2014      Published: August 21, 2014 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 (p70 S6K ), which is a downstream effector of mammalian target of rapamycin, is frequently hyperactivated in human ovarian cancer. Here, we identified p70 S6K 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 p70 S6K 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 p70 S6K in tumor spheroid-mesothelium communication in ovarian cancer and provide a preclinical rationale for targeting p70 S6K as a new avenue for microenvironment-based therapeutic strategy.