|
| Status |
Public on Jun 01, 2023 |
| Title |
Cancer-specific alternative polyadenylation shapes tumor phenotypes in vivo |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
|
| Summary |
Alternative polyadenylation (APA) is strikingly dysregulated in many cancers. Although APA dysregulation is frequently associated with poor prognosis, the biological importance of most APA events remains unclear simply because few have been functionally studied. Here, we performed a CRISPR/Cas9-based screen to assess individual APA events’ contributions to tumor growth in vivo. Forcing use of specific polyadenylation sites altered mRNA and protein levels to modify mouse melanoma growth in an immunocompetent host. Our screen highlighted APA events of potential clinical relevance. For example, forced Atg7 3′ UTR lengthening in mouse melanoma reduced ATG7 protein levels and tumor immune infiltration; similarly, in human melanoma, a long ATG7 3′ UTR and low mRNA levels were significantly associated with reduced anti-tumor T cell activity and failure of immune checkpoint blockade. Our data demonstrate that cancer-associated APA plays a causative role in tumorigenesis and motivate future studies of the therapeutic potential of modulating APA.
|
| |
|
| Overall design |
Comparative Poly(A) sequencing for B16-F10 melanoma and Melan-A cells (melanocyte cell line) completed 6x replicates. RNA-seq of 3x cells and 5x tumors of B16-F10 Cas9-expressing cells treated with a paired-guide RNA that force 3' UTR lengthening in the gene Atg7, relative to a control unexpressed gene (Crabp1).
|
| |
|
| Contributor(s) |
Gabel AM, Bradley RK |
| Citation(s) |
38302465 |
| |
| Submission date |
Aug 29, 2022 |
| Last update date |
Feb 14, 2024 |
| Contact name |
Austin Max Gabel |
| E-mail(s) |
agabel1@uw.edu
|
| Phone |
4102922554
|
| Organization name |
Fred Hutchinson Cancer Center
|
| Department |
Computational Biology
|
| Lab |
Robert K. Bradley
|
| Street address |
1100 Fairview Ave. N., B3-111
|
| City |
Seattle |
| State/province |
WA |
| ZIP/Postal code |
98109 |
| Country |
USA |
| |
|
| Platforms (1) |
|
| Samples (12)
|
|
| Relations |
| BioProject |
PRJNA874754 |
Less...
More...