Issue No. 39, June 2021
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine, VCU and external experts focusing on important medically-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.     
Pharmacological Inhibition of MDA-9/Syntenin Blocks Breast Cancer Metastasis Through Suppression of IL-1β
 
A recent discovery published in PNAS by Dr. Fisher’s group in collaboration with VIMM members Drs. Das, Emdad, Landry, Wang and Sarkar have demonstrated that MDA-9/Syntenin provides a direct therapeutic target for aggressive breast cancer and a small-molecule inhibitor, PDZ1i, provides a promising molecule for inhibiting advanced breast cancer pathogenesis.
 
Highlights of the study:
 
  • Genetic silencing of MDA-9/Syntenin or treatment with a pharmacological inhibitor of the PDZ1 domain, PDZ1i, activates the immune system to kill cancer cells.

  • Additionally, suppression of MDA-9/Syntenin deregulates myeloid-derived suppressor cell (MDSC) differentiation via the STAT3/interleukin (IL)-1β pathway, which concomitantly promotes activation of cytotoxic T lymphocytes.

  • Biologically, PDZ1i treatment decreases metastatic nodule formation in the lungs, resulting in significantly fewer invasive cancer cells.

Breast cancer remains the second leading cause of death among women in the United States. Prognosis for early-stage disease is favorable, whereas late-stage disease with tumor cell spread beyond the primary site (i.e., metastasis) frequently heralds poorer outcomes. Therapy of metastatic disease usually involves systemic chemotherapy combined with radiation, providing mostly palliative options to reduce metastatic outgrowth. Multiple unique and distinct biological steps and an interplay between transformed and nontransformed cells highlight complexities of the metastatic process, which habitually thwarts clinical intervention. Targeting these processes independently or collectively could culminate in effective antimetastatic therapies.
 
Melanoma differentiation-associated gene-9 (mda-9), also known as Syntenin-1 or syndecan binding protein (SDCBP), was originally discovered by Dr. Fisher’s laboratory using subtraction hybridization from terminal differentiating metastasis-derived human melanoma cells treated with interferon (IFN)-β and the protein kinase C activator, mezerein (designated as mda-9/Syntenin). Preferential elevated expression of MDA-9/Syntenin is evident in histologically distinct tumors and contributes to several steps in the metastatic process. These include tumor cell invasion and migration, induction of angiogenesis through secretion of proangiogenic factors, enhancement of epithelial–mesenchymal transition , regulation of the expression of integrins affecting cell-adhesion processes, exosome biogenesis and exosome-mediated signaling in cell–cell communication, and recently immune-modulation suppressing host immune-surveillance. Based on its relevance to the invasive and metastatic phenotype of cancers, MDA-9/Syntenin represents a prospective target for rational design of antimetastatic drugs. Perturbing MDA-9/Syntenin protein:protein interactions is viewed as a viable strategy to disrupt key downstream signaling pathways regulating cancer cell invasion and metastasis. Fragment-based drug discovery guided by NMR identified a first in-class interaction inhibitor of the PDZ1 domain of MDA-9/Syntenin, PDZ1i, and displaying efficacy against glioblastoma multiforme, neuroblastoma, and prostate cancer. PDZ1i suppresses cancer cell-autonomous and nonautonomous functions of MDA-9/Syntenin, culminating in strong antiinvasive and antimetastatic properties in vitro and in vivo, without inducing overt cytostatic or toxic effects in normal or most cancer cells.
 
New research from Dr. Fisher’s group with VIMM collaborators published in PNAS explored a potential role of MDA-9/Syntenin in breast cancer progression with specific emphasis on a relevant interleukin, IL-1β, representing an important inflammatory cytokine mediating cancer pathogenesis and tumor progression. Inflammation regulates fundamental pathways that are causative of the cancer phenotype, including proliferation, survival, and migration. The research demonstrates that MDA-9/Syntenin regulates tumor-specific expression of IL-1β and other proinflammatory cytokines mediated by STAT3, and enhances MDSC infiltration producing immune suppression (Fig. 1). Blocking MDA-9/Syntenin with PDZ1i impedes breast cancer metastasis in syngeneic animals, reversing the immunosuppressive effects in the metastatic breast cancer niche providing therapeutic benefit against metastatic breast cancer.
Figure 1. Schematic of the Role of MDA-9/Syntenin in Immune Suppression and Reversal of Suppression by PDZ1i. In tumor cells, MDA-9/Syntenin mediates activation of STAT3 resulting in secretion of IL-1β that fosters mobilization of MDSCs in the tumor niche, establishing an immunosuppressive environment. PDZ1i, selectively inhibits MDA-9/Syntenin signaling, thereby obstructing the STAT3/IL-1β pathway preventing MDSCs accumulation and consequently altering the dynamics of immunosuppression, preventing metastatic breast cancer cell growth.
 
Publication:
 
* Pradhan AK, Maji S, Bhoopathi P, Talukdar S, Mannangatti P, Guo C, Wang XY, Cartagena LC, Idowu M, Landry JW, Sarkar D, Emdad L, Cavenee WK, Das SK, Fisher PB. Pharmacological inhibition of MDA-9/Syntenin blocks breast cancer metastasis through suppression of IL-1β. Proc Natl Acad Sci U S A. 2021 May 25;118(21):e2103180118. PMID: 34016751 PMCID: PMC8166168 (available on 2021-11-20). DOI: 10.1073/pnas.2103180118
  
About the Investigators: Paul B. Fisher, MPh, PhD, FNAI, is Professor and Chair of the VCU Department 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. Anjan K. Pradhan, PhD, is an Instructor in the Department of Human and Molecular Genetics (HMG), the first author of this paper, and performed much of the biological and animal work. Santanu Maji, PhD is a postdoc in HMG. Praveen Bhoopathi, PhD and Sarmistha Talukdar, PhD are Instructors in HMG. Chunqing Guo, PhD, is an Assistant Professor in HMG. Swadesh K. Das, PhD, Luni Emdad, MBBS, PhD, Joseph W. Landry, PhD are Associate Professors in HMG and Members of the VIMM. Webster K. Cavenee, PhD is the Director of Strategic Alliances in Central Nervous System Cancers from Ludwig Institute for Cancer Research, UCSD, San Diego, CA, USA. Devanand Sarkar, MBBS, PhD and Xiang-Yang Wang, PhD are Professors in HMG and Associate Directors of Cancer Therapeutics and Immunology, respectively, in the VIMM.. Lorraine Colon Cartagena, MD, and Michael Idowu, MD are from Department of Pathology, Virginia Commonwealth University. The study was supported in part by NIH/National Cancer Institute (NCI) Grants R01 CA244993 (to D.S. and P.B.F.) and CA099326 and CA229812 (to X.-Y.W.); Department of Defense Grant W81XWH1910489 (to J.W.L.); NCI Cancer Center Support Grant to the Virginia Commonwealth University (VCU) Massey Cancer Center (MCC) P30 CA016059 (to Robert Winn); the National Foundation for Cancer Research (W.K.C. and P.B.F.); and a Sponsored Research Agreement between VCU and InVaMet Therapeutics (to S.K.D.). P.B.F. holds the Thelma Newmeyer Corman Chair in Cancer Research at the MCC. D.S. is the Harrison Foundation Distinguish Professor in Cancer Research at the MCC. X.-Y.W. holds the Harry and Judy Wason Chair in Cancer Research at the MCC. Services and products in support of the research project were generated by the VCU MCC Flow Cytometry Shared Resource and Cancer Mouse Models Core Laboratory, supported, in part, with funding from NIH/NCI Cancer Center Support Grant P30 CA016059.