Geminin overexpression-dependent recruitment and crosstalk with mesenchymal stem cells enhance aggressiveness in triple negative breast cancers

// Suryatheja Ananthula 1 , Abhilasha Sinha 1 , Mohamed El Gassim 1 , Simran Batth 2 , Gailen D. Marshall Jr. 2 , Lauren H. Gardner 3 , Yoshiko Shimizu 4 , Wael M. ElShamy 1 1 Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA 2 Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA 3 Institute for Biogenesis Research, Cancer Center, University of Hawaii, Honolulu, HI, USA 4 Clinical and Translational Research Program, Cancer Center, University of Hawaii, Honolulu, HI, USA Correspondence to: Wael M. ElShamy, e-mail: welshamy@umc.edu Keywords: breast cancer, triple negative, geminin, c-Abl, HMGB1 Received: September 22, 2015      Accepted: February 16, 2016      Published: March 10, 2016 ABSTRACT Resident mesenchymal stem cells (MSCs) promote cancer progression. However, pathways and mechanisms involved in recruiting MSCs into breast tumors remain largely undefined. Here we show that geminin-dependent acetylation releases HMGB1 from the chromatin to the cytoplasm and extracellular space. Extracellular acetylated HMGB1 (Ac-HMGB1) promotes geminin overexpressing (GemOE) cells survival by binding to RAGE and activating NF-κB signaling. Extracellular Ac-HMGB1 also triggers expression and activation of RAGE in the non-expressing MSCs. RAGE activation induces expression of CXCR4 in MSCs and directional migration towards SDF1 ( aka CXCL12)-expressing GemOE cells in vitro and in vivo . These effects augmented by the necrotic and hypoxic environment in GemOE tumors, especially within their cores. Reciprocal interactions between newly recruited MSCs and GemOE tumor cells elevate tumor-initiating (TIC), basal and epithelial-to-mesenchymal transition (EMT) traits and enhance aggressiveness in vitro and in vivo in GemOE tumor cells. Indeed, faster, larger and more aggressive tumors develop when GemOE cells are co-injected with MSCs in orthotopic breast tumor model. Concurrently, inhibiting c-Abl (and thus geminin function), RAGE or CXCR4 prevented MSCs recruitment to GemOE cells in vitro and in vivo , and decreased the TIC, basal and EMT phenotypes in these tumor cells. Accordingly, we propose that GemOE tumor cells present within tumor cores represent metastatic precursors, and suppressing the GemOE→HMGB1/RAGE→SDF1/CXCR4 signaling circuit could be a valid target for therapies to inhibit GemOE tumors and their metastases.