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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Dec 29, 2023 |
| Title |
suppression of Pyruvate carboxylase in E0771 tumors [in vivo] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Metabolic reprogramming an immune evasion are established hallmarks of the tumor microenvironment (TME). Growing evidence supports tumor metabolic dysregulation as an important mediator of tumor immune evasion. High TME levels of lactate potently suppress antitumor immunity. Pyruvate carboxylase (PC), responsible for the anaplerotic conversion of pyruvate to oxaloacetate, is essential for lung metastasis in breast cancer. Conversely, PC may be dispensable in some cells in the TME, with loss of PC associated with immunosuppression. Here we test whether PC suppression alters tumor metabolism and immunosuppression. Using multiple animal models of breast cancer, we identify a dimorphic role for PC expression in mammary cancer cells. PC supports metastatic colonization of the lungs; however, depletion of PC promotes primary tumor growth and suppresses histological and transcriptomic markers of antitumor immunity. We demonstrate that PC is potently suppressed by hypoxia, and that PC suppression is common in solid tumors, particularly those with higher levels of hypoxia. Using metabolomics, high resolution respirometry, and extracellular flux analysis, we show that PC-depleted cells produce more lactate and undergo less oxidative phosphorylation than scramble controls. Finally, we identify lactate metabolism as a targetable dependency of PC-depleted cells, which is sufficient to restore T cell populations to the TME of PC-depleted tumors. Taken together these data demonstrate that elevated lactate following PC suppression by hypoxia may be a key mechanism through which primary tumors limit antitumor immunity. Thus, these data highlight PC directed tumor metabolism is a nexus of tumor progression and antitumor immunity.
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| Overall design |
11 E0771 tumors transduced with scramble control or PC targeting shRNA (scram n=4, shPC25 n=3, shPC28 n=4)
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| Contributor(s) |
Coleman MF, Hursting SD |
| Citation(s) |
38849928 |
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| Submission date |
Mar 30, 2022 |
| Last update date |
Jun 28, 2024 |
| Contact name |
michael francis coleman |
| E-mail(s) |
mcoleman@unc.edu
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| Phone |
9199850347
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| Organization name |
UNC
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| Street address |
235 dauer drive
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| City |
chapel hill |
| State/province |
North Carolina |
| ZIP/Postal code |
27516 |
| Country |
USA |
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| Platforms (1) |
| GPL24242 |
[Clariom_S_Mouse_HT] Affymetrix Clariom S Assay HT, Mouse (Includes Pico Assay) |
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| Samples (11)
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| GSM5988111 |
E0771 tumor excised from C57BL6J mouse_LFD SCR 1 |
| GSM5988112 |
E0771 tumor excised from C57BL6J mouse_LFD SCR 2 |
| GSM5988113 |
E0771 tumor excised from C57BL6J mouse_LFD SCR 3 |
| GSM5988114 |
E0771 tumor excised from C57BL6J mouse_LFD SCR 4 |
| GSM5988115 |
E0771 tumor excised from C57BL6J mouse_LFD SHPC 25 1 |
| GSM5988116 |
E0771 tumor excised from C57BL6J mouse_LFD SHPC 25 2 |
| GSM5988117 |
E0771 tumor excised from C57BL6J mouse_LFD SHPC 25 3 |
| GSM5988118 |
E0771 tumor excised from C57BL6J mouse_LFD SHPC 28 1 |
| GSM5988119 |
E0771 tumor excised from C57BL6J mouse_LFD SHPC 28 2 |
| GSM5988120 |
E0771 tumor excised from C57BL6J mouse_LFD SHPC 28 3 |
| GSM5988121 |
E0771 tumor excised from C57BL6J mouse_LFD SHPC 28 4 |
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| This SubSeries is part of SuperSeries: |
| GSE199831 |
suppression of Pyruvate carboxylase |
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| Relations |
| BioProject |
PRJNA821608 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE199829_RAW.tar |
11.6 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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