Multiplexed screening reveals how cancer-specific alternative polyadenylation shapes tumor growth in vivo

Austin M. Gabel, Andrea E. Belleville, James D. Thomas, Siegen A. McKellar, Taylor R. Nicholas, Toshihiro Banjo, Edie I. Crosse and Robert K. Bradley ()
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Austin M. Gabel: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center
Andrea E. Belleville: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center
James D. Thomas: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center
Siegen A. McKellar: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center
Taylor R. Nicholas: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center
Toshihiro Banjo: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center
Edie I. Crosse: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center
Robert K. Bradley: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Alternative polyadenylation (APA) is strikingly dysregulated in many cancers. Although global APA dysregulation is frequently associated with poor prognosis, the importance of most individual APA events is controversial simply because few have been functionally studied. Here, we address this gap by developing a CRISPR-Cas9-based screen to manipulate endogenous polyadenylation and systematically quantify how APA events contribute to tumor growth in vivo. Our screen reveals individual APA events that control mouse melanoma growth in an immunocompetent host, with concordant associations in clinical human cancer. For example, forced Atg7 3′ UTR lengthening in mouse melanoma suppresses ATG7 protein levels, slows tumor growth, and improves host survival; similarly, in clinical human melanoma, a long ATG7 3′ UTR is associated with significantly prolonged patient survival. Overall, our study provides an easily adaptable means to functionally dissect APA in physiological systems and directly quantifies the contributions of recurrent APA events to tumorigenic phenotypes.

Date: 2024
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DOI: 10.1038/s41467-024-44931-x

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