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| Status |
Public on Jun 03, 2022 |
| Title |
Melanoma GEMM Tumors, untreated or vemurafenib treated [bulk RNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Emerging research suggests that multiple tumor compartments can influence treatment responsiveness and relapse, yet the search for therapeutic resistance mechanisms remains largely focused on acquired genomic alterations in cancer cells. Here, we show how treatment-induced changes occur in multiple tumor compartments during tumor relapse and can reduce benefit of follow-on therapies. By utilizing serial biopsies, next generation sequencing and single cell transcriptomics, we tracked the evolution of multiple cellular compartments within individual lesions during first-line treatment response, relapse and second-line therapeutic interventions in an autochthonous model of melanoma. We discovered that while treatment-relapsed tumors remained genetically stable, they converged on a shared resistance phenotype characterized by dramatic changes in tumor cell differentiation state, immune infiltration and extracellular matrix (ECM) composition. Similar alterations in tumor cell differentiation were also observed in more than half of our treatment-relapsed patient tumors. Tumor cell state changes were coincident with ECM remodeling and increased tumor stiffness, which alone was sufficient to alter tumor cell fate and reduce treatment responses in melanoma cell lines in vitro. Despite the absence of acquired mutations in the targeted pathway, resistant tumors showed significantly decreased responsiveness to second-line therapy intervention within the same pathway. The ability to preclinically model relapse and refractory settings - while capturing dynamics within and crosstalk between all relevant tumor compartments - provides a unique opportunity to better design and sequence appropriate clinical interventions.
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| Overall design |
bulk RNA-seq
This study is related to GSE126714.
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| Contributor(s) |
Juntilla MR, Nickles D |
| Citation(s) |
30824837 |
| |
| Submission date |
Jun 01, 2022 |
| Last update date |
Sep 05, 2022 |
| Contact name |
Dorothee Nickles |
| E-mail(s) |
nicklesd@gene.com
|
| Organization name |
Genentech
|
| Street address |
1 DNA Way
|
| City |
South San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94080 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (34)
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| This SubSeries is part of SuperSeries: |
| GSE205294 |
Melanoma GEMM Tumors, untreated or vemurafenib treated |
|
| Relations |
| BioProject |
PRJNA844272 |
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