In-vivo CRISPR Screen Identifies Mitoferrin-1 as a Microenvironment-Dependent Liability for Metastasis

Cancer cells that metastasize to distant organs must adapt their metabolism to the new nutrient environment.

However, we lack a comprehensive understanding of how different organ microenvironments influence the nutrient dependencies of metastases. We performed a pooled loss-of-function CRISPR screen of 407 solute carrier (SLC) transporters in an experimental mouse model of breast cancer metastasis to define differences in nutrient utilization between metastasizing cancer cells in the lung and liver. Interestingly, we find that intracellular SLC transporters were more often identified as important for metastasis growth than plasma membrane transporters. One of the highest ranking intracellular SLC transporters we identify as a requirement for liver but not lung metastases growth is mitoferrin-1 (Slc25a37), which transports iron into the mitochondria. Mitoferrin-1 loss almost completely ameliorates liver metastasis in experimental models of mouse and human breast cancer metastasis. Consequently, high tumoral mitoferrin-1 expression is associated with liver metastasis in breast cancer patients. Functionally, we discover that mitoferrin-1 enables cancer cells to grow in less perfused tissue areas, which is especially important in the highly zonated liver. Accordingly, we observe that hypoxia and HIF1α stabilization in the liver induce mitoferrin-1 expression to promote heme synthesis. While the requirement of heme cofactors for hypoxia-induced proteins has been described, we unexpectedly find that cancer cells utilize heme in hypoxia to support production of the potent lipophilic antioxidant, bilirubin. Furthermore, inhibiting heme or bilirubin synthesis in metastasizing cancer cells in-vivo promotes lipophilic ROS accumulation and ferroptosis in low oxygen microenvironments. Treating mice with the ferroptosis inhibitor, Liproxstatin-1, rescues mitoferrin-1 deficient liver metastasis growth. In summary, we identify several axes of heme metabolism that could be exploited for enhanced detection or treatment of patients with liver metastasis.

Authors

Alejandro M. Cuadros (1,2), Ines Vermeire(1,2), Dorien Broekaert(1,2), Juan Fernandez-Garcia(1,2), Thomas Van Brussel(3), Tatjana Geukens(4), Maxim De Schepper(4), Yentl Lambrechts(5), Sigrid Hatse (5), Hans Wildiers(5), Christine Demedt(4), Diether Lambrechts(3), and Sarah-Maria Fendt(1,2)

Organisations

(1) Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium (2) Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium (3) Laboratory for translational genetics (VIB-KULeuven) Herestraat 49, Box 912 ON IV, 3000 Leuven Belgium (4) Laboratory for Translational Breast Cancer Research, Department of Oncology, Herestraat 49 - box 815 3000 Leuven, Belgium (5) University Hospitals Leuven and Department of Oncology, Herestraat 49 - box 815 3000 Leuven, Belgium

Presenting author

Alejandra Cuadros, Doctoral Researcher - KUL Biomedical Sciences, VIB-KU Leuven Center for Cancer Biology
alex.cuadros@kuleuven.be
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