Issue No. 16, April 2018
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, M.Ph., Ph.D., the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by the VIMM members.     
Swadesh K. Das, PhD
Paul B. Fisher, MPh, PhD
Research from VIMM Scientists Establishes the Importance of
MDA-9/Syntenin/IGF1R/STAT3 Axis in PC Progression

  • Prostate cancer (PC) is one of the most commonly diagnosed non-cutaneous cancer malignancies affecting men worldwide.
  • Patients diagnosed at an advanced stage usually die within 12 to 18 months, primarily due to metastasis and lack of appropriate therapeutic approaches. 
  • A recent study by VIMM scientists demonstrates a positive correlation between MDA-9/Syntenin and advanced stages of PC using clinical samples and cancer cell lines.
  • This research identified Insulin-like growth factor 1-receptor (IGF-1R) as a novel binding partner of MDA-9/Syntenin in a PC context. Interaction of MDA-9/Syntenin with IGF-1R activates STAT3, resulting in upregulation of various invasion/angiogenesis-associated genes, ultimately facilitating the invasion process.
  • Conceptual and experimental approaches developed by Drs. Swadesh K. Das and Paul B. Fisher confirm a unique mechanism of action of MDA-9/Syntenin (SDCBP) in PC pathogenesis. This work paves the way for therapies delimiting prostate cancer development and metastasis.

MDA-9/Syntenin as a Potential Mediator of PC Progression

Prostate cancer (PC) is one of the most commonly diagnosed non-cutaneous cancer malignancies affecting men worldwide. Patients diagnosed at an advanced stage usually die within 12 to 18 months, primarily due to metastasis and lack of appropriate therapeutic approaches. Thus, understanding the pathobiology of PC is pivotal for developing curative therapy. MDA-9/Syntenin was cloned by the Fisher laboratory in 1993 and is receiving attention for its central pathogenic role in multiple, diverse cancers. The current study provides important conceptual advances through in vitro and in vivo experiments of PC invasion and how MDA-9/Syntenin regulates this process. 

Functionally, MDA-9/Syntenin cancer-promoting activity depends to a significant extent on interaction with specific partner proteins. The research identified IGF-1R as a novel binding partner of MDA-9/Syntenin in a PC context. IGFBP-2, a direct downstream target of MDA-9/Syntenin, plays a crucial role in establishing this interaction and its downstream effects. Interaction of MDA-9/Syntenin with IGF-1R activates STAT3, resulting in upregulation of various invasion/angiogenesis-associated genes, which ultimately facilitate the invasion process. The study links these two distinct pathways for the first time and addresses why IGFBP-2 is upregulated and how IGF-1R and STAT3 are activated. In summary, this innovative study has now resolved multiple research questions in PC and identified the critical components of invasion signaling, which may serve as molecular targets for future clinical intervention.
Figure legend: A. Representative photomicrographs of MDA-9/Syntenin expression in various stages of prostate adenocarcinoma. Staining intensity was measured using imaging software and the average value with standard deviation for Stage II and III disease is presented. B, Hypothetical model of MDA-9/Syntenin-mediated PC progression.
The present research was supported in part by funding from NIH grant 635 P50 CA058236 (P.B. Fisher and Martin G. Pomper) and NCI Cancer Center Support Grant to VCU Massey Cancer Center P30 CA016059 (P.B. Fisher and D. Sarkar), the National Foundation for Cancer Research (NFCR, to P.B. Fisher), the Human and Molecular Genetics Enhancement Fund (to S.K. Das and L. Emdad), VCU Massey Cancer Center (MCC) developmental funds (to P.B. Fisher), and VCU Institute of Molecular Medicine (VIMM) developmental funds (to P.B. Fisher, S.K. Das, and L. Emdad). The study was published in Cancer Research March 23rd, 2018*.
Publications:
* Das SK, Pradhan AK, Bhoopathi P, Talukdar S, Shen XN, Sarkar D, Emdad L, Fisher PB. The MDA-9/Syntenin/IGF-1R/STAT3 axis directs prostate cancer invasion. Cancer Res. 2018 Mar 23. pii: canres.2992.2017. PMID:29572229 DOI:10.1158/0008-5472.CAN-17-2992

About the Investigators: Paul B. Fisher, MPh, PhD, is Professor and Chair of Human and Molecular Genetics (HMG), Director of the VCU Institute of Molecular Medicine (VIMM) and Thelma Newmeyer Corman Chair in Cancer Research in the VCU Massey Cancer Center (MCC), Virginia Commonwealth University, School of Medicine, Richmond, VA. Swadesh K. Das, PhD, an Assistant Professor in HMG and Member of the VIMM, is the first and co-corresponding author of this paper. Luni Emdad, MBBS, PhD is Assistant Professor in HMG and Member of the VIMM. Devanand Sarkar is an Associate Professor in HMG, Associate Scientific Director of Therapeutics in the VIMM, and a Harrison Foundation Distinguished Professor in Cancer Research in the VCU MCC. Praveen Bhoopathi, PhD, Anjan Pradhan, PhD and Sarmistha Talukdar, PhD are postdoctoral research scientists in HMG. Xue-Ning Shen, MD, is a senior technician in the Fisher laboratory performing animal studies.