Stephan J. Reshkin

Our laboratory focuses on three major areas: What molecular and biochemical mechanisms are responsible for triggering tumor cell invasion and metastatic implantation and growth? How do the stromal and metabolic microenvironments influence the biology of the tumor with particular attention to invasion and metastasis? What are the signal transduction systems that regulate the invasive ‘program’ driven by the tumor microenvironments? For these purposes we have developed a number of techniques to analyze invasion, the organelle used to invade, invadopodia, and to ‘recreate’ in vitro 3D models of the metastatic microenvironment to study metasatatic mechanisms and therapeutic strategies.

Figure: ImmunoHistoFluorescence for EGFR (blue), NHE1 (green) and NHERF1 (red) and hematoxylin and eosin (H&E) staining in pancreatic tissues derived from mice in which the three human PDAC cell lines were orthotopically implanted. Areas of EGFR/NHERF1/NHE1, EGFR/NHE1 and NHERF1/NHE1 co-localization are in white (insets labeled a), cyan (insets labeled c) or orange (insets labeled b). As the tumors are formed from ever more metastatic cell lines (BXPC3>PANC1>MIAPACA-2) the protein-protein complexes made-up of the three proteins become more separated from the trimer complex (almost 100% in BXPC3) into the EGFR/NHE1 and NHERF1/NHE1 dimer complexes.

 

IonTraC project: An EGFR-based therapy targeting the NHERF1-EGFR-NHE1 axis

 

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Relevant publications:

Reshkin SJ, Cardone RA, Greco MR, Zeeberg K, Harguindey S. 2014. Na+-H+ Exchanger, pH Regulation and Cancer. Recent Pat Anticancer Drug Discovery, eBook (In Press) 

Greco MR, Antelmi E, Busco G, Guerra L, Rubino R, Casavola V, Reshkin SJ, Cardone RA. 2014. Protease activity at invadopodial focal digestive areas is dependent on NHE1-driven acidic pHe. Oncology Reports. 31:940-946 

Reshkin SJ, Greco MR and Cardone RA. 2014. Role of pHi, and proton transporters in oncogene-driven neoplastic transformation. Philosophical Transactions of the Royal Society B- Biological Sciences. Feb 3;369(1638):20130100. doi: 10.1098/rstb.2013.0100.

Antelmi E, Cardone RA, Greco MR, Rubino R, Di Sole F, Martino NA, Casavola V, Carcangiu M, Moro L, Reshkin SJ. 2013. ß1 integrin binding phosphorylates ezrin at T567 to activate a lipid raft signalsome driving invadopodia activity and invasion. PloS ONE 8(9): e75113. doi:10.1371/journal.pone.0075113

Brisson L, Driffort V, Benoist L, Poet M, Counillon L, Antelmi E, Rubino R, Besson P, Labbal F, Chevalier S, Reshkin SJ, Gore J and Roger S. 2013. NaV1.5 sodium channels allosterically regulate the NHE-1 exchanger and promote breast cancer cell invadopodial activity. J. Cell Sci. 126:4835-4842.

Mangia A, Saponaro C, Malfettone A, Bisceglie D, Bellizzi A, Asselti M, Popescu O, Reshkin SJ, Paradiso A, Simone G. 2012. Involvement of nuclear NHERF1 in colorectal cancer progression. Oncol Rep. 28(3):889-984.