JGM, Female, Humans, Breast Neoplasms, Carcinogenesis, Oncogenes, Proto-Oncogene Proteins c-myc, RNA Splicing, RNA Splicing Factors
Cell Rep. 2022;41(8):111704
We thank Drs. Chuang, Graveley, Pinter, Carmichael, and Lau for helpful dis- cussions; Dr. Helenius for manuscript edits; Drs. Muthuswamy and Liu for MCF-10A and HCC1806 cells; and C. Chatzipantsiou and A.D. Mays for assis- tance with pipeline cloud implementation. We acknowledge the Microscopy, Single Cell Biology, and Genome Technologies Cores at The Jackson Labora- tory (JAX) supported by the JAX Cancer Center (NCI P30CA034196). This work was supported by NIH grants R00CA178206, R01CA248317, R01GM138541,and T32AG062409A. We acknowledge the use of data generated by TCGA, managed by NCI and NHGRI, downloaded using ISB Cancer Genome Cloud and processed using Google Cloud Platform Research Credits.
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, but the mechanistic links between MYC and the splicing machinery in cancer remain underexplored. Here, we identify a network of co-expressed splicing factors (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 induces MYC-regulated splicing events and increases organoid size and invasiveness, while knockdown decreases organoid size. Finally, we uncover a MYC-activity pan-cancer splicing signature correlating with survival across tumor types. Our findings provide insight into the mechanisms of MYC-regulated splicing and for the development of therapeutics for MYC-driven tumors.
MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors. Cell Rep. 2022;41(8):111704
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).