Proteomic Analysis of Colorectal Cancer Metastasis: Stathmin-1 Revealed as a Player in Cancer Cell Migration and Prognostic Marker
JOURNAL OF PROTEOME RESEARCH
Authors: Tan, Hwee Tong; Wu, Wei; Ng, Yi Zhen; Zhang, Xuxiao; Yan, Benedict; Ong, Chee Wee; Tan, Sandra; Salto-Tellez, Manuel; Hooi, Shing Chuan; Chung, Maxey C. M.
Abstract
Metastasis accounts largely for the high mortality rate of colorectal cancer (CRC) patients. In this study, we performed comparative proteome analysis of primary CRC cell lines HCT-116 and its metastatic derivative E1 using 2-D DIGE. We identified 74 differentially expressed proteins, many of which function in transcription, translation, angiogenesis signal transduction, or cytoskeletal remodeling pathways, which are indispensable cellular processes involved in the metastatic cascade. Among these proteins, stathmin-1 (STMN1) was found to be highly up-regulated in E1 as compared to HCT-116 and was thus selected for further functional studies. Our results showed that perturbations in STMN1 levels resulted in significant changes in cell migration, invasion, 4 adhesion, and colony formation. We further showed that the differential expression of STMN1 correlated with the cells' metastatic potential in other paradigms of CRC models. Using immunohistochemistry, we also showed that STMN1 was highly expressed in colorectal primary tumors and metastatic tissues as compared to the adjacent normal colorectal tissues. Furthermore, we also showed via tissue microarray analyses of 324 CRC tissues and Kaplan-Meier survival plot that CRC patients with higher expression of STMN1 have poorer prognosis.
A PDGFR alpha-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine
NATURE COMMUNICATIONS
Authors: Jun, Hyun Jung; Appleman, Vicky A.; Wu, Hua-Jun; Rose, Christopher M.; Pineda, Javier J.; Yeo, Alan T.; Delcuze, Bethany; Lee, Charlotte; Gyuris, Aron; Zhu, Haihao; Woolfenden, Steve; Bronisz, Agnieszka; Nakano, Ichiro; Chiocca, Ennio A.; Bronson, Roderick T.; Ligon, Keith L.; Sarkaria, Jann N.; Gygi, Steve P.; Michor, Franziska; Mitchison, Timothy J.; Charest, Al
Abstract
Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFR alpha and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFR alpha, and the analysis of GBM signaling pathways using proteomics. We discover the tubulin-binding protein Stathmin1 (STMN1) as a PDGFR alpha phospho-regulated target, and that this mis-regulation confers sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFR alpha-positive mouse and a patient-derived xenograft (PDX) GBMs with VB in mice prolongs survival and is dependent on STMN1. Our work reveals a previously unconsidered link between PDGFR alpha activity and STMN1, and highlight an STMN1-dependent cytotoxic effect of VB in GBM.