Gilad Silberberg, Yaron Mosesson, Haia Khoury, Xuan Ren, Mara Gilardi, Art Hanson, Marianna Zipeto, Michael Ritchie
The lack of knowledge around the mechanisms underlying metastatic progression is a major hurdle in achieving a durable response in the treatment of metastatic breast cancer (BC). Accordingly, effective therapies are not yet available, and the treatment of metastatic BC remains an unmet critical medical need. Circulating BC cancer cells can colonize the lungs, bone, brain, and liver generating metastatic lesions, which lead to poor outcomes. Liver metastases account for 30% of metastatic BC cases, therefore causing the greatest therapeutic challenge. The first line of therapy for BC liver metastasis is typically an invasive surgical resection, which unfortunately does not always resolve the metastatic lesion and requires further treatment. Unfortunately, there is currently no therapeutic standard of care (SOC) for BC liver metastasis, and therapy is selected based on the molecular profiling of primary tumor and metastasis biopsies. The scarcity of reliable and biologically relevant human experimental models, to provide a deep understanding of the molecular interactions underlying metastasis, is warranted.
In this study, we exploit multiomic interrogation of breast cancer patient-derived xenografts (PDX) models established from primary lesions, and metastasis of the liver, to uncover the molecular mechanisms underlying BC cells liver colonization. The results highlight global molecular differences between models derived from primary BC tumors and BC lesions collected from the liver. The analysis also reveals several genes at the DNA, RNA, and protein expression/activity levels aiding in the adaptation of BC cell colonization in the liver. These novel findings provide insight into novel mechanisms of BC liver metastasis and highlight several targets suitable for future therapeutic intervention.