The Oncogenic PI3K-Induced Transcriptomic Landscape Reveals Key Functions in Splicing and Gene Expression Regulation.
The Oncogenic PI3K-Induced Transcriptomic Landscape Reveals Key Functions in Splicing and Gene Expression Regulation.
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DOI：
10.1158/0008-5472.can-22-0446
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发表时间：
2022-06-15
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影响因子：
11.2
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转录组学分析揭示了PI3K通路在调控RNA剪接中具有关键作用，发现了PI3K在乳腺癌中调控增殖和代谢的新机制。
磷脂酰肌醇3 - 激酶（PI3K）通路调控增殖、存活和代谢，在人类癌症中经常被激活。全面阐明该信号通路如何控制转录和共转录过程，可以为PI3K信号在癌症中的关键功能提供新的见解。在此，我们采用转录组学方法研究PI3K下游的全基因组基因表达和转录因子活性变化，以及剪接和异构体使用动态。这些分析揭示了在PIK3CA突变细胞中与增殖、代谢和剪接相关的广泛可变剪接异构体，这些异构体可通过抑制PI3Kα而逆转。对接受PI3Kα抑制剂治疗的PIK3CA突变乳腺癌患者的配对肿瘤活检样本进行分析，发现了广泛的剪接改变，这些改变影响与临床前模型相同的特定异构体，并且这些改变，即PTK2/FRNK和AFMID异构体，被验证为癌细胞生长或迁移的功能性驱动因素。从机制上讲，异构体特异性剪接因子介导了PI3K依赖的RNA剪接。使用剪接抑制剂治疗使乳腺癌细胞对PI3Kα抑制剂阿培利司更加敏感，导致比单独使用阿培利司更强的生长抑制。这项研究首次全面分析了致癌PI3K在乳腺癌中驱动的广泛剪接改变。PI3K介导的剪接程序图谱确立了PI3K通路在调控剪接中的关键作用，为利用PI3K信号作为乳腺癌的治疗靶点开辟了新途径。
转录组学分析揭示了PI3K通路在调控RNA剪接中具有关键作用，发现了PI3K在乳腺癌中调控增殖和代谢的新机制。
参见克拉里奇和霍普金斯的相关评论，第2216页
观看对2023年癌症研究早期职业奖获得者恩eda·托斯卡博士的采访：https://vimeo.com/847434965
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. 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. 2216 Watch the interview with Eneda Toska, PhD, recipient of the 2023 Cancer Research Early Career Award: https://vimeo.com/847434965