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| Status |
Public on Jun 28, 2024 |
| Title |
Hypoxic Memory Mediates Prolonged Tumor Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression [scRNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, hypoxia downregulated tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a “hypoxic memory” phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor (HDACi) entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for CTCs during the metastatic cascade.
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| Overall design |
Single cell RNAseq profiling of tumors from 12 or 16-weeks old FVB-MMTV-PyMT mice. N=2 for each timepoint.
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| Contributor(s) |
Chin C, Iriondo O, Klotz R, Yu M |
| Citation(s) |
38990731 |
| |
| Submission date |
Jun 20, 2024 |
| Last update date |
Oct 01, 2024 |
| Contact name |
Christopher Russell Chin |
| E-mail(s) |
[email protected]
|
| Phone |
3393640514
|
| Organization name |
Weill Cornell
|
| Lab |
Melnick Lab
|
| Street address |
413 E 69th Street, Belfer Building, BB-1462
|
| City |
New York City |
| State/province |
NY |
| ZIP/Postal code |
10021 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE270903 |
Hypoxic Memory Mediates Prolonged Tumor Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression |
|
| Relations |
| BioProject |
PRJNA1126152 |
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