STAT3 and cancer: In agreement, as described in Supplementary Figure S1, when STAT3 was silenced, CAL27 and SCC-15 cells lost a significant degree of ability to generate tumor spheres and the EVs released from STAT3-silenced tumor spheres, contained a lower level of β-catenin, TGFβ1 and miR-21-5p; these observations strongly suggest that inhibiting signaling networks such as STAT3/β-catenin, associated with the generation of cancer stem cells, could lead to the reduced oncogenic cargos released into the TME.