Fibroblasts in the establishment of the liver pre-metastatic niche

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PROJECT SUMMARY Postpartum breast cancer (PPBC), defined as breast cancer diagnosed within 10 years after a women's last childbirth, accounts for 50% of young women's breast cancer cases. PPBC patients have a 52% 5-year survival rate, whereas age-matched non-PPBC patients have an 80% 5-year survival rate. In rodent studies, supported by patient data, PPBC cases have a greater affinity to progress to overt metastasis after a diagnosis of locally contained disease. Specifically, we find that stage I-III PPBC patients progress to liver metastasis more often than non-PPBC patients. Liver metastasis is a devastating prognosis with only a 3–15-month median survival rate. In rodent models and humans, weaning-induced mammary gland involution has been shown to be a niche that supports establishment of circulating tumor cells in the PPBC patient, and eventual progression to overt metastatic disease. Rodent studies, supported by human studies, show evidence that the liver undergoes remodeling post-weaning, much like the mammary gland. Rodent models of PPBC liver metastasis, support that this remodeling, known as liver involution, establishes a pro-tumor environment, and may account for the increased liver metastasis seen in PPBC patients. This proposal seeks to understand mechanisms by which liver involution supports the liver metastasis niche. Specifically, the proposed aims will explore the role of liver fibroblasts in establishing a unique pre-metastatic niche in the postpartum period during weaning-induced liver involution. While pro-tumor involution fibroblasts have been reported in the mammary gland, it is unknown if liver fibroblasts differentially respond to environmental cues during involution or if they contribute to the establishment of a pro-metastatic niche. Aim 1 will identify and describe distinct populations of fibroblasts across a reproductive cycle using single-cell RNAseq and multiplex immunohistochemistry (mIHC). Liver fibroblast populations will then be functionally tested to investigate if involution liver fibroblasts are tumor promotional. During the K00 phase I will transition into understanding liver fibroblasts in the establishment of liver pre- metastatic niches in breast and pancreatic cancer, with a focus on fibroblast-immune cell-crosstalk. Little is known about how liver fibroblasts respond to tumor education of the pre-metastatic niche. My K00 proposal will investigate if liver fibroblasts alter their antigen presentation to promote immune cell dysfunction over the course of pre-metastatic niche education. This proposal will expand upon my knowledge of liver fibroblasts, and allow me to strength my knowledge of other cancer fields, such as cancer immunology. The research project and training plan proposed in this application will give me the skills and knowledge I need to pursue a career as an independent investigator.