RT Journal Article
SR Electronic
T1 MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.24.469558
DO 10.1101/2021.11.24.469558
A1 Laura Urbanski
A1 Mattia Brugiolo
A1 SungHee Park
A1 Brittany Angarola
A1 Nathan K. Leclair
A1 Phil Palmer
A1 Sangram Keshari Sahu
A1 Olga Anczuków
YR 2021
UL http://biorxiv.org/content/early/2021/11/24/2021.11.24.469558.abstract
AB MYC is dysregulated in >50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, a hallmark of cancer, but the mechanistic links between MYC and the splicing machinery remain underexplored. Here, we identify a network of splicing factors (SFs) co-expressed as SF-modules in MYC-active breast tumors. Of these, one is a pan-cancer SF-module, correlating with MYC-activity across 33 tumor types. In mammary cell models, MYC activation leads to co-upregulation of pan-cancer module SFs and to changes in >4,000 splicing events. In breast cancer organoids, co-overexpression of the pan-cancer SF-module is sufficient to induce splicing events that are also MYC-regulated in patient tumors and to increase organoid size and invasiveness, while its knockdown decreases organoid size. Finally, we uncover a pan-cancer splicing signature of MYC activity which correlates with survival in multiple tumor types. Our findings provide insight into the mechanisms and function of MYC-regulated splicing and for the development of therapeutics for MYC-driven tumors.Competing Interest StatementThe authors have declared no competing interest.