Loss‐of‐function screens of druggable targetome against cancer stem‐like cells

Abstract

Cancer stem–like cells (CSLCs) contribute to the initiation and recurrence of tumors and to their resistance to conventional therapies. In this study, small interfering RNA (siRNA)-based screening of ∼4800 druggable genes in 3-dimensional CSLC cultures in comparison to 2-dimensional bulk cultures of U87 glioma cells revealed 3 groups of genes essential for the following: survival of the CSLC population only, bulk-cultured population only, or both populations. While diverse biologic processes were associated with siRNAs reducing the bulk-cultured population, CSLC-eliminating siRNAs were enriched in a few functional categories, such as lipid metabolism, protein metabolism, and gene expression. Interestingly, siRNAs that selectively reduced CSLC only were found to target genes for cholesterol and unsaturated fatty acid synthesis. The lipidomic profile of CSLCs revealed increased levels of monounsaturated lipids. Pharmacologic blockage of these target pathways reduced CSLCs, and this effect was eliminated by addition of downstream metabolite products. The present CSLC-sensitive target categories provide a useful resource that can be exploited for the selective elimination of CSLCs.—Song, M., Lee, H., Nam, M.-H., Jeong, E., Kim, S., Hong, Y., Kim, N., Yim, H. Y., Yoo, Y.-J., Kim, J. S., Kim, J.-S., Cho, Y.-Y., Mills, G. B., Kim, W.-Y., Yoon, S. Loss-of-function screens of druggable targetome against cancer stem–like cells.

STARD13 is positively correlated with good prognosis and enhances 5-FU sensitivity via suppressing cancer stemness in hepatocellular carcinoma cells

“…Since tumor cell stemness could lead to tumor recurrence and chemoresistance, 12 we speculated that STARD13 over-expression could attenuate HCC cell stemness. Based on the fact that nonadherent spheres are highly enriched for CSC, 13 and as STARD13 expression displayed relative lower level in HepG2 and Huh7 cells compared with other HCC cell lines ( Figure 1D ), HepG2 and Huh7 cells were chosen for the following experiments.…”

Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome

“…Reprogramming and hijacking of existing metabolic pathways to sustain energetic and biosynthetic needs is a well-established characteristic of cancer cells, but it seems that CSCs are even more efficient in this process compared to more differentiated cancer cells. In a recent large siRNA screening study in which $4,800 druggable genes were analyzed in a 3D culture setting, cholesterol biosynthesis and synthesis of unsaturated fatty acids pathways were found to be the only selective CSC druggable targets (Song et al, 2017). Inhibition of the mevalonate pathway with farnesyltransferase inhibitors (FTIs) or HMG-CoA reductase inhibitors (statins) has shown promise in preclinical breast cancer studies.…”

Evodiamine Eliminates Colon Cancer Stem Cells via Suppressing Notch and Wnt Signaling

“…To find druggable pathways that target CSCs and BCCs together, we performed siRNA screening and revealed several potential targets [9]. Several metabolic pathways may act as vulnerable selective CSC targets were identified.…”