1. State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
2. Department of Breast Reconstruction, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, China.
3. National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Treatment of Tianjin, Tianjin Clinical Research Center for Cancer.
4. Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
5. Department of Pathology, Tianjin First Center Hospital, Tianjin 300192, China.
6. Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430022, China.
7. The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, 100005, Beijing, China.
8. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
* Q. Li, X. Lv and C. Han contributed equally to this study.
Rationale: Cancer associated fibroblasts (CAFs) are a subpopulation of cells within the tumor microenvironment that usually promote cancer progression and metastasis. Hence it is critical to find out the driving factors and mechanisms for the development of CAFs from normal fibroblasts (NFs) in response to sustained stimulation of cancer cells. Here we perform transcriptomic and epigenomic analyses in paired NFs and CAFs associated with breast cancer metastasis to investigate the molecular mechanisms for stromal fibroblasts reprogramming.
Methods: We conducted transcriptomic analyses in paired NFs and CAFs isolated from clinical specimens of breast cancer patients with metastasis. Meanwhile, genome-wide mapping of histone marks H3K4me1 and H3K27ac was also performed to characterize CAF-specific enhancer landscape. The function and mechanisms of activated JUN in stromal fibroblasts were studied using in vitro and in vivo models.
Results: We have identified CAF-specific signature genes and activated enhancers, which are significantly associated with pro-metastatic programs. Among the CAF activated enhancers, FOS and JUN family of transcription factors are enriched. In line with this, we find that JUN protein is highly activated in the stroma of metastatic breast cancers. And through gain and loss-of-function studies, we demonstrate that activated JUN is necessary and sufficient to remodel enhancers and maintain the activation of CAF-specific enhancers, and thereby promotes breast cancer invasiveness in a non-cell-autonomous manner.
Conclusions: Our study gets an insight into the transcriptomic features of invasive breast stroma and transcription regulatory mechanisms for stroma cell transformation, providing a proof-of-concept of stroma-targeting strategy in cancer treatment.
Keywords: cancer-associated fibroblasts, metastasis, enhancers, transcription factors, JUN