Targeting AXL and RAGE to prevent geminin overexpression-induced triple-negative breast cancer metastasis

Dissemination of metastatic precursors from primaries is the primary reason for patient death. Dissemination encompasses tumor cells invasion of stroma, followed by intravasation through the endothelium barrier into the bloodstream. Here, we describe how geminin-overexpressing tumor cells acquire dissemination ability. Acetylated HMGB1 (Ac-HMGB1) secreted by geminin-overexpressing cells activates RAGE and CXCR4 expression on mesenchymal stem cells (MSCs) located in tumor stroma. Through secreting CXCL12, geminin-overexpressing cells recruit these CXCR4⁺-MSCs into the tumor. Within the tumor, MSCs differentiate into S100A4-secreting cancer-associated fibroblasts (CAFs). S100A4, in a reciprocal manner, activates geminin-overexpressing cells to secrete CCL2 that recruits M0-macrophages from the stroma into the tumor. Within the tumor, CCL2 polarizes M0-macrophages into Gas6-secreting M2-tumor-associated macrophages (M2-TAMs). In concert, geminin-overexpression, S100A4/RAGE and Gas6/AXL signaling promote the invasive and intravasation abilities in geminin-overexpressing cells through exacerbating their stemness and epithelial-to-mesenchymal phenotypes and enhancing expression and functional interaction of CD151 and α3β1-integrin in geminin-overexpressing cells. Tumors formed following injection of geminin-overexpressing cells admixed with MSCs/CAFs grew faster, metastasized earlier, especially to lungs, and were extremely sensitive to anti-c-Abl, anti-RAGE, and anti-AXL drugs. These data support an intrinsic ability in geminin-overexpressing tumor cells to promote their metastatic potential through recruitment and bi-directional interactions with MSCs/CAFs and M2-TAMs.