Authors
Garcia-Lerena, J., Jhan, J.-R., Talukdar, N., Vusich, J., Ortiz, M., Schulte, A., Atkins, M., Patel, D., Hollern, D., Quackenbush, M., To, B., Marei, S., WangL, H., Lu, Y., Kiki-Teboum, T., Flick, M., Chen, B., Luyendyk, J., Andrechek, E.
Abstract
Metastasis is the leading cause of death in breast cancer, yet the mechanisms controlling organotropism are not well defined. Coagulation has emerged as a biologically relevant contributor to metastatic progression, but mechanisms linking pro-thrombotic phenotypes to organ-specific metastasis remain unresolved, significantly hindering the development of novel treatments. Here, a serial transplantation approach was used to enrich for liver organotropism from a spontaneous mouse mammary tumor model with occasional liver and lymph node metastasis. Comparative transcriptomics between the enriched liver and lymph node metastases revealed strong upregulation of coagulation in liver metastases, due in part to loss of repression of FXII with knockout of the E2F5 transcription factor. In vitro clotting assays demonstrated that tumor-derived FXII was sufficient to induce fibrin(ogen) clot formation. Moreover, liver metastatic cells exhibit elevated lipid peroxide levels and impaired lipid droplet formation associated with a pro-coagulant phenotype. Inhibition of coagulation with low molecular weight heparin reduced the presence of circulating tumor cells and suppressed liver metastasis in the mouse model. Human electronic health record data supported the translational relevance of these findings. Together, these data identify a tumor cell intrinsic E2F5-FXII axis that activates host coagulation as a functional determinant to enhance liver-specific metastasis in breast cancer.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 09 Jun 2026.
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