He, Xue-Yan, Ng, David, Gao, Yuan, Michalopoulou, Evdokia, George, Shanu, Adrover, Jose M, Sun, Lijuan, Albrengues, Jean, Wan, Ledong, Han, Xiao, Vakoc, Christopher, Van Aelst, Linda, Egeblad, Mikala (2023) Untangling the connection between stress and metastatic breast cancer. In: American Association for Cancer Research Annual Meeting 2023, 2023 Apr 14-19, Orlando, FL.
Abstract
There is emerging evidence that exposure to chronic stress is associated with increased risk of metastasis and poor survival in cancer patients. However, the underlying molecular and cellular mechanisms responsible for the effects of stress on tumor progression remain unclear. To determine how stress promotes metastasis, we established new mouse models in which multiple chronic stress exposure promoted breast cancer metastasis to the lungs. We found that chronic stress generates a pro-metastatic lung microenvironment with e.g., reduced T cell infiltration and increased extracellular matrix (ECM) deposition and neutrophil infiltration. Among them, neutrophils were required for these changes as their depletion abolished the pro-metastatic effects of stress and normalized the lung tumor microenvironment. Mechanistically, we analyzed neutrophils from chronically stressed mice and identified dramatically altered transcriptomes, including increased expression of several glucocorticoid receptor regulated genes. Phenotypically, neutrophils from stress exposed mice exhibited increased ROS production, and an increased ability to inhibit T cell activation and to form spontaneous neutrophil extracellular traps (NETs). The stress-associated changes to neutrophils were dependent on glucocorticoid receptor (GR) signaling as neutrophil-specific GR knockout mice showed no increase in NET-formation, a normalized lung microenvironment and no increase in lung metastasis upon stress exposure. Among the changes in the neutrophils caused by stress exposure, we found that the formation of pro-metastatic NETs was critical as directly digesting NETs with DNase I prevented stress-induced metastasis and normalized the lung microenvironment. In sum, this work shows that chronic stress exposure causes a glucocorticoid-mediated increase in NET formation and that NETs are critical drivers in the establishment of a stress-induced, metastasis-promoting microenvironment. Targeting NETs could be an important strategy to prevent metastatic recurrence in cancer patients, many of whom will experience stress due to their cancer diagnosis and subsequent treatments.
| Item Type: | Conference or Workshop Item (Poster) |
|---|---|
| Subjects: | organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells diseases & disorders > cancer > cancer types > breast cancer organism description > animal behavior > stress |
| CSHL Authors: | |
| Communities: | CSHL labs > Egeblad lab CSHL labs > Krainer lab CSHL labs > Vakoc lab CSHL labs > Van Aelst lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2023 |
| Date Deposited: | 27 Sep 2023 15:19 |
| Last Modified: | 27 Sep 2023 15:25 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/40996 |
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