Hepatic stellate cell activation in the postpartum liver is consistent with pre-metastatic niche establishment

Abstract

Postpartum breast cancer (PPBC), diagnosed within 10 years of the last childbirth, has an increased risk of liver metastasis. In murine models, tumor transplant studies reveal that weaning-induced liver involution is a key determinant of breast cancer metastasis to the liver. Here we explored potential mechanisms by which hepatic stellate cells (HSCs), the tissue-resident liver fibroblasts, contribute to pre-metastatic niche formation immediately following weaning. We characterized normal murine liver involution and breast cancer metastasis to the liver using mIHC, bulk RNAseq, and scRNAseq approaches. In non-tumor-bearing mice, post-wean HSCs activation was confirmed by increased expression of ECM (Col3, Col5, and fibronectin), and increased expression of immune regulatory gene signatures when compared to nulliparous mice. Mammary tumor cells injected into the portal vein of InvD2 mice developed liver lesions with increased stromal attributes, when compared to nulliparous hosts, consistent with fibroblast activation. When isolated HSCs were mixed with mammary tumor cells and subcutaneously injected, InvD4-HSC group tumors were larger, desmoplastic, and enriched for regulatory immune cells when compared to the nulliparous-HSC tumors. These findings illuminate how HSCs are activated during weaning-induced liver involution, consistent with the establishment of a pre-metastatic niche, and underscore the translational potential of targeting HSCs to improve outcomes for PPBC patients.