American Association for Cancer Research
Browse

Supplementary Table from The Oncogenic PI3K-Induced Transcriptomic Landscape Reveals Key Functions in Splicing and Gene Expression Regulation

Download (2.35 MB)
dataset
posted on 2023-03-31, 05:24 authored by Erik Ladewig, Flavia Michelini, Komal Jhaveri, Pau Castel, Javier Carmona, Lauren Fairchild, Adler G. Zuniga, Amaia Arruabarrena-Aristorena, Emiliano Cocco, Ryan Blawski, Srushti Kittane, Yuhan Zhang, Mirna Sallaku, Laura Baldino, Vasilis Hristidis, Sarat Chandarlapaty, Omar Abdel-Wahab, Christina Leslie, Maurizio Scaltriti, Eneda Toska
Supplementary Table from The Oncogenic PI3K-Induced Transcriptomic Landscape Reveals Key Functions in Splicing and Gene Expression Regulation

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

Find out more...

Breast Cancer Research Foundation (BCRF)

V Foundation

National Science Foundation (NSF)

Innovation to Cancer Informatics

Jayne Koskinas Ted Giovanis

Breast Cancer Research Alliance

History

ARTICLE ABSTRACT

The phosphoinositide 3–kinase (PI3K) pathway regulates proliferation, survival, and metabolism and is frequently activated across human cancers. A comprehensive elucidation of how this signaling pathway controls transcriptional and cotranscriptional processes could provide new insights into the key functions of PI3K signaling in cancer. Here, we undertook a transcriptomic approach to investigate genome-wide gene expression and transcription factor activity changes, as well as splicing and isoform usage dynamics, downstream of PI3K. These analyses uncovered widespread alternatively spliced isoforms linked to proliferation, metabolism, and splicing in PIK3CA-mutant cells, which were reversed by inhibition of PI3Kα. Analysis of paired tumor biopsies from patients with PIK3CA-mutated breast cancer undergoing treatment with PI3Kα inhibitors identified widespread splicing alterations that affect specific isoforms in common with the preclinical models, and these alterations, namely PTK2/FRNK and AFMID isoforms, were validated as functional drivers of cancer cell growth or migration. Mechanistically, isoform-specific splicing factors mediated PI3K-dependent RNA splicing. Treatment with splicing inhibitors rendered breast cancer cells more sensitive to the PI3Kα inhibitor alpelisib, resulting in greater growth inhibition than alpelisib alone. This study provides the first comprehensive analysis of widespread splicing alterations driven by oncogenic PI3K in breast cancer. The atlas of PI3K-mediated splicing programs establishes a key role for the PI3K pathway in regulating splicing, opening new avenues for exploiting PI3K signaling as a therapeutic vulnerability in breast cancer. Transcriptomic analysis reveals a key role for the PI3K pathway in regulating RNA splicing, uncovering new mechanisms by which PI3K regulates proliferation and metabolism in breast cancer.See related commentary by Claridge and Hopkins, p. 2216Watch the interview with Eneda Toska, PhD, recipient of the 2023 Cancer Research Early Career Award: https://vimeo.com/847434965

Usage metrics

    Cancer Research

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC