Hypothetical model for SOX11/CXCR4/FAK axis regulating MCL cell migration, crosstalk with the protective stromal microenvironment, progressive growth, and resistance to conventional treatments. SOX11 directly regulates CXCR4 and PTK2/FAK gene transcription, also influenced by tumor microenvironment factors. CXCR4 overexpression in SOX11⁺ MCL cells and CXCL12 secretion by stromal cells at the tumor microenvironment enhance p-FAK at Y397, promoting MCL cell migration and adhesion to BM and LNs in a SOX11-dependent manner. The SOX11/CXCR4/FAK axis in MCL cells promotes crosstalk with BM stromal cells for protective microenvironment interactions through the activation of the PI3K/AKT and ERK1/2 FAK-downstream signaling pathways that contribute to stromal-induced cell proliferation, survival, and drug resistance (CAM-DR). Targeting FAK, CXCR4/CXCL12, and/or PI3K pathways could constitute new therapeutic strategies to disrupt the protective microenvironment interactions in relapsed/refractory aggressive MCL.