|
| Status |
Public on Dec 31, 2019 |
| Title |
Hotspot mutations induce metabolic reprogramming and vulnerability to serine deprivation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Cancer-associated mutations in the spliceosome gene create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we provide evidence that aberrant splicing by mutant alters the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also find that mutant induces vulnerability to deprivation of the nonessential amino acid serine, which is mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability is manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice is able to inhibit the growth ofMUT xenografts. These findings describe a novel role for mutations in altered energy metabolism, and they offer a new therapeutic strategy againstMUT cancers.
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| |
|
| Overall design |
Four mutant MCF10A replicates (two from the K700E1 clone and two from K700E2) and four wild type replicates (two from R702R1 and two from TWT1) were compared.
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| |
|
| Contributor(s) |
Dalton WB, Park BO |
| Citation(s) |
31393856 |
| |
| Submission date |
Jul 18, 2019 |
| Last update date |
Apr 16, 2020 |
| Contact name |
William Brian Dalton |
| E-mail(s) |
wbriandalton@gmail.com
|
| Phone |
410-614-6173
|
| Organization name |
Johns Hopkins University School of Medicine
|
| Department |
Oncology
|
| Lab |
Division of Hematologic Malignancies
|
| Street address |
1650 Orleans St.
|
| City |
Baltimore |
| State/province |
Maryland |
| ZIP/Postal code |
21231 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL15456 |
Illumina HiScanSQ (Homo sapiens) |
|
| Samples (8)
|
|
| Relations |
| BioProject |
PRJNA555220 |
| SRA |
SRP215215 |
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