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| Status |
Public on Jan 01, 2020 |
| Title |
Sphingosine kinase 2 in stromal fibroblasts creates a hospitable tumor microenvironment in breast cancer |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Reciprocal interactions between breast cancer cells and the tumor microenvironment are important for cancer progression and metastasis. We report here that the deletion or inhibition of sphingosine kinase 2 (SphK2), which produces sphingosine-1-phosphate (S1P), markedly suppresses syngeneic breast tumor growth and lung metastasis in mice by creating a hostile microenvironment for tumor growth and invasion. SphK2 deficiency decreased S1P and concomitantly increased ceramides, including C16-ceramide, in stromal fibroblasts. Ceramide accumulation suppressed activation of cancer-associated fibroblasts (CAFs) by upregulating stromal p53, which restrained production of tumor-promoting factors to reprogram the tumor microenvironment and restrict breast cancer establishment. Ablation of p53 in SphK2-deficient fibroblasts reversed these effects, enabled CAF activation and promoted tumor growth and invasion. These data uncovered a novel role of SphK2 in regulating non-cell autonomous functions of p53 in stromal fibroblasts and their transition to tumor-promoting CAFs, paving the way for the development of a strategy to target the tumor microenvironment and enhance therapeutic efficacy.
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| Overall design |
mRNA expression profiles of wild type and SphK2 null mouse embryonic fibroblasts were determined in triplicate using Illumina.
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| Contributor(s) |
Weigel C, Maczis MA, Paladino E, Green CD, Maceyka M, Guo C, Wang X, Dozmorov MG, Milstien S, Spiegel S |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Aug 29, 2019 |
| Last update date |
Oct 20, 2023 |
| Contact name |
Mikhail Dozmorov |
| E-mail(s) |
mdozmorov@vcu.edu
|
| Organization name |
Virginia Commonwealth University
|
| Department |
Biostatistics
|
| Street address |
830 E Main St
|
| City |
Richmond |
| State/province |
VA |
| ZIP/Postal code |
23298 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL15103 |
Illumina HiSeq 1000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA562928 |
| SRA |
SRP219855 |
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