K. Pietras (Lund, Sweden)
Lund UniversityAuthor Of 1 Presentation
19P - A dichotomous oncogenic role of the splicing factor SF3A3 in MYC-driven Triple Negative Breast Cancer.
Abstract
Background
Splicing is a central RNA-based process commonly altered in human cancers; however, how spliceosomal components are co-opted during tumorigenesis remains poorly defined. Previous work on MYC-driven triple negative breast cancer (TNBC) has revealed the spliceasome as an essential vulnerability that can be targeted to achieve disease control. Therefore, an important outstanding question is the contribution of individual components of the spliceosome machinery to the tumorigenic process downstream of MYC hyperactivation.
Methods
Our data is supported by extensive mechanistic analysis of spliceosome regulatory dynamics using both in vitro and in vivo models as well as patient material (RNA seq and tissue microarray of a cohort of TNBC patients as well as publicly available datasets).
Results
We unravel that specific spliceosomal components are translationally regulated during oncogenic stress. Indeed, we found that MYC enables SF3A3 translation through an eIF3D-dependent mechanism. This ensures accurate splicing of mRNAs enriched for mitochondrial regulators. Altered SF3A3 translation leads to metabolic reprogramming and stem-like properties that fuel MYC tumorigenic potential in vivo. Furthermore, SF3A3 protein analysis reveals a dichotomous role associated with MYC activity in triple negative breast cancers. Our analysis of human TNBC patient samples provides strong evidence that SF3A3 post-transcriptional regulation is associated with unique gene expression signatures that stratify the clinical outcomes in these patients.
Conclusions
These findings unveil a post-transcriptional interplay between splicing and translation that governs critical facets of MYC-driven oncogenesis.
Legal entity responsible for the study
The authors.
Funding
Swedish Foundations’ Starting Grant StemTherapy, Swedish Research Council (Vetenskapsrådet), Swedish Cancer Society (Cancerfonden) and the Fru Berta Kamprad Foundation.
Disclosure
A. Bosch: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Novartis; Travel/Accommodation/Expenses: Roche. All other authors have declared no conflicts of interest.