|
| Status |
Public on Oct 15, 2017 |
| Title |
Gene expression profiles of Ofd1 and Kif3a mutant SMB21 cells generated by CRISPR knockout |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Drug resistance poses a great challenge to targeted cancer therapies. In Hedgehog pathway-dependent cancers, the scope of mechanisms enabling resistance to Smo-inhibitors is not known. Here, we performed a transposon mutagenesis screen in medulloblastoma and identified multiple modes of resistance. Surprisingly, mutations in ciliogenesis genes represent a frequent cause of resistance, and patient datasets indicate that cilia loss constitutes a clinically relevant category of resistance. Conventionally, primary cilia are thought to enable oncogenic Hedgehog signaling. Paradoxically, we find that cilia loss protects tumor cells from susceptibility to Smo-inhibitors and maintains a “persister” state that depends on continuous low output of the Hedgehog program. Persister cells can serve as a reservoir for further tumor evolution, as additional alterations synergize with cilia loss to generate aggressive recurrent tumors. Together, our findings reveal novel patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance.
|
| |
|
| Overall design |
mRNA profiles of CRISPR-GFP (3 biological replicates), CRISPR-Ofd1 (3 biological replicates) and CRISPR-Kif3a (2 biological replicates) cells
|
| |
|
| Contributor(s) |
Zhao X, Segal RA |
| Citation(s) |
28923910 |
| |
| Submission date |
Sep 06, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Xuesong Zhao |
| E-mail(s) |
xuesong_zhao@dfci.harvard.edu
|
| Phone |
6176326174
|
| Organization name |
Dana-Farber Cancer Institute
|
| Department |
Cancer Biology
|
| Lab |
Rosalind Segal
|
| Street address |
450 Brookline Ave
|
| City |
Boston |
| State/province |
Massachusetts |
| ZIP/Postal code |
02215 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (7)
|
|
| This SubSeries is part of SuperSeries: |
| GSE103538 |
A transposon screen identifies loss of primary cilia as a mechanism of resistance to Smo inhibitors |
|
| Relations |
| BioProject |
PRJNA401822 |
| SRA |
SRP117032 |
Less...
More...