Title | Flura-seq identifies organ-specific metabolic adaptations during early metastatic colonization. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Basnet H, Tian L, Ganesh K, Huang Y-H, Macalinao DG, Brogi E, Finley LWs, Massagué J |
Journal | Elife |
Volume | 8 |
Date Published | 2019 03 26 |
ISSN | 2050-084X |
Abstract | Metastasis-initiating cells dynamically adapt to the distinct microenvironments of different organs, but these early adaptations are poorly understood due to the limited sensitivity of in situ transcriptomics. We developed fluorouracil-labeled RNA sequencing (Flura-seq) for in situ analysis with high sensitivity. Flura-seq utilizes cytosine deaminase (CD) to convert fluorocytosine to fluorouracil, metabolically labeling nascent RNA in rare cell populations in situ for purification and sequencing. Flura-seq revealed hundreds of unique, dynamic organ-specific gene signatures depending on the microenvironment in mouse xenograft breast cancer micrometastases. Specifically, the mitochondrial electron transport Complex I, oxidative stress and counteracting antioxidant programs were induced in pulmonary micrometastases, compared to mammary tumors or brain micrometastases. We confirmed lung metastasis-specific increase in oxidative stress and upregulation of antioxidants in clinical samples, thus validating Flura-seq's utility in identifying clinically actionable microenvironmental adaptations in early metastasis. The sensitivity, robustness and economy of Flura-seq are broadly applicable beyond cancer research. |
DOI | 10.7554/eLife.43627 |
Alternate Journal | Elife |
PubMed ID | 30912515 |
PubMed Central ID | PMC6440742 |
Grant List | P01-CA094060 / NH / NIH HHS / United States K08-CA230213 / NH / NIH HHS / United States T32 CA009207 / CA / NCI NIH HHS / United States T32-CA009207 / NH / NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States W81XWH-12-0074 / / Department of Defense / International DR-12998 / DRCRF / Damon Runyon Cancer Research Foundation / United States K08 CA230213 / CA / NCI NIH HHS / United States F30-CA203238 / NH / NIH HHS / United States P01 CA094060 / CA / NCI NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States T32-GM07739 / NH / NIH HHS / United States F30 CA203238 / CA / NCI NIH HHS / United States |
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