How Cancers Rewire RNA Splicing to Sustain Oncogenic Signaling

David M. Walter, PhD
Research Fellow
Department of Medical Oncology
Dana-Farber Cancer Institute

Department of Genetics
Harvard Medical School
Boston, MA, USA
 

This conference is hosted by Mathieu Ferron, PhD, Director of the Molecular Physiology Research Unit.

About this conference
U2AF1^S34F is one of the most common somatic amino acid substitutions in lung adenocarcinoma; however, the mechanism by which this splicing factor mutation contributes to lung cancer pathogenesis is not well understood. I have leveraged prime editing to institute U2AF1^S34F mutations in A549 lung adenocarcinoma cells, and identified a novel alternative splicing event in KRAS, whereby exon 2 is skipped in ~20% of transcripts in KRAS^G12S-mutant A549 cells. This exon-skipping event results in a dysfunctional KRAS protein, ultimately reducing KRAS signaling and cell growth. However, KRAS exon 2 inclusion is restored upon U2AF1^S34F mutation, leading to increased MAPK signaling and the positive selection of U2AF1^S34F mutations in KRAS^G12S-mutant LUADs. I also discovered a similar phenomenon, whereby KRAS^Q61R and KRAS^Q61L mutations lead to KRAS exon 3 skipping, which restricts MAPK signaling. However, the acquisition of mutant U2AF1^I24T rescues KRAS exon 3 inclusion, leading to a strong enrichment of U2AF1^I24T mutations in pancreatic cancers with KRAS^Q61R or KRAS^Q61L mutations. As such, my research has described a novel mechanism for the positive selection of splicing factor mutations in solid tumors: correcting splicing defects that arise inadvertently due to oncogenic mutations.

About David M. Walter
Dr. David Walter is originally from Toronto and obtained his Bachelor of Science from Queen’s University. He then went on to perform his PhD training in the laboratory of Dr. David Feldser at the University of Pennsylvania. There he used genetically engineered mouse models to study tumour suppressor functions in lung adenocarcinoma. He is currently a Damon Runyon Fellow in the laboratory of Dr. Matthew Meyerson at Dana-Farber Cancer Institute, where he is investigating the role of splicing factor mutations in solid tumours.

To make sure you don't miss any of the IRCM conferences, sign up now for our newsletter!