This invention discloses a method of modulating the survival and stemness of cancer stem cells (CSCs) by modulating the expression of MDA-9/Syntenin (SDCBP), which regulates multiple stemness genes, and controls survival of CSCs by activating the pathways, including without limitation NOTCH1. In one embodiment, the stemness genes that can be regulated by modulating expression or activity of MDA-9/Syntenin (SDCBP) includes, but are not limited to, ALDH1A1, AXL, CD44, DDR1, ID1, ITGB1, c-myc, Nanog, NOTCH, Oct4/POU5F1, Sox2, and STAT3. The invention also discloses a method of decreasing/inhibiting CSCs's tumorigenicity and a method of increasing survival of a subject with cancer by suppression of mda-9. This invention provides a method of inhibiting the growth of a cancer, and a method of determining the metastatic or angiogenic potential of a cancer. This invention further provides a method of screening for a candidate compound that modulate the expression or activities of MDA-9/Syntenin (SDCBP).