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.     

Research from VIMM scientists establish a link between MDA-9/Syntenin and protective autophagy in anoikis-resistance identifying an Achilles’ heel of glioblastoma multiforme

MDA-9/Syntenin facilitates anoikis-resistance in GBM

Glioblastoma multiforme (GBM) is the most frequent and aggressive glial tumor, containing a small population of unique therapy-resistant cells, glioma stem cells (GSCs). Current dogma suggests that tumor regrowth originates from GSCs, and these cells contribute to resistance to therapy, poor prognosis, and recurrence. Thus, understanding the pathobiology of GSCs is essential for developing curative therapy. MDA-9/Syntenin was cloned by the Fisher laboratory in 1993 and is receiving increasing attention for its central pathogenic role in multiple, diverse cancers. The current study provides important conceptual advances through in vitro and in vivo experiments on GSC survival in extremely stressful conditions and how MDA-9/Syntenin regulates this process. 

Functionally, MDA-9/Syntenin’s cancer-promoting activity depends to a significant extent on interactions with specific partner proteins. This research identified a pivotal and novel function of MDA-9/Syntenin in the regulation and maintenance of anoikis-resistant GSCs through protective autophagy. Anoikis-resistant GSCs express significantly higher levels of MDA-9/Syntenin vs. anoikis-sensitive non-stem glioma cells. MDA-9/Syntenin expression regulates EGFR activation and PKCα signaling-mediated antiapoptotic BCL2 protein phosphorylation through FAK in an interconnected and interdependent manner. PKC controls survival in GSCs, by regulating the antiapoptotic protein BCL2. EGFR maintains autophagy levels via regulation of ATG5, LC3, and Lamp1, so autophagy does not exceed threshold levels, resulting in a shift from cell viability to toxicity. This complex and interconnected process maintains protective autophagy in GSCs, thereby protecting against anoikis. When loss of MDA-9/Syntenin occurs, this delicate balance is disrupted causing autophagy levels to exceed the threshold level, thereby shifting autophagy from protective to toxic. In summary, this innovative study has demonstrated a link between MDA-9, protective autophagy and anoikis-resistance, identifying a potential vulnerability of glioblastoma multiforme that may be exploited to define enhanced therapeutic strategies for future clinical intervention.

Figure legend: A. Representative electron microscopy images of GSCs showing autolysosome morphology in cytoprotective autophagy in sh con vs. cytotoxic autophagy in sh mda- 9 treated VG2 GSCs expressing EGFR wt and mutated EGFRvIII (with constitutively active EGFR signaling). Constitutive activation of EGFR shows decreased autophagic vesicle formation. sh con GSCs show basal and healthy level of autophagy, whereas sh mda- 9 neurospheres show highly elevated expression of autophagic vesicles. B. Hypothetical model of MDA-9/Syntenin-regulated protective autophagy and anoikis resistance mechanism in GSCs.

This research was supported by the National Foundation for Cancer Research (to P.B. Fisher and W.K. Cavenee), the Virginia Commonwealth University Institute of Molecular Medicine (P.B. Fisher), and the Genetics Enhancement Fund (to P.B. Fisher, S.K. Das, and L. Emdad). The study was published in the Proceedings of the National Academy of Sciences of the United States of America May 14, 2018*.

Publications:

Talukdar S, Das SK, Pradhan AK, Emdad L, Shen XN, Windle JJ, Sarkar D, Fisher PB. Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells. Oncotarget. 2016 Aug 23;7(34):54102-54119. PMCID: PMC5342330.

* Talukdar S, Pradhan AK, Bhoopathi P, Shen XN, August LA, Windle JJ, Sarkar D, Furnari FB, Cavenee WK, Das SK, Emdad L, Fisher PB. MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells. Proc Natl Acad Sci U S A. 2018 May 14. pii: 201721650. PMID: 29760085 DOI:10.1073/pnas.1721650115. 

About the Investigators: Paul B. Fisher, MPh, PhD, FNAI, 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. Sarmistha Talukdar, PhD, is the first author of this research study, and along with Anjan Pradhan, PhD and Praveen Bhoopathi, PhD are postdoctoral research scientists in HMG. Swadesh K. Das, PhD, and Luni Emdad, MBBS, PhD are Assistant Professors in HMG and Members 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. Jolene J. Windle, PhD, is a Professor at HMG and directs the Massey Cancer Center/VCU Transgenic/Knockout Mouse Core Laboratory. Xue-Ning Shen, MD, is a senior technician in the Fisher laboratory performing animal studies. Laura A. August, BS, is a research technician in the Fisher laboratory. Frank Furnari, PhD is Professor of Pathology at UCSD and a Member of Ludwig Institute of Cancer Research, UCSD. Webster K. Cavenee, PhD is Director of Strategic Alliances in Central Nervous System (CNS) Cancers, Distinguished Professor UCSD and Member of the Ludwig Institute of Cancer Research, UCSD.