Spatiotemporal modeling of chemoresistance evolution in breast tumors uncovers dependencies on SLC38A7 and SLC46A1

• DOI: 10.1016/j.celrep.2023.113191
• Publication Date: 2023-10-04T05:13:50Z
• Authors: Yannick Audet-Delage; Catherine St-Louis; Lucía Minarrieta; Shawn McGuirk; Irwin Kurreal; Matthew G. Annis; Arvind Singh Mer; Peter M. Siegel; Julie St-Pierre
• Keywords: Drug Resistance, Neoplasm; Animals; Humans; Female; Breast Neoplasms; Mammary Neoplasms, Animal; Breast; Proton-Coupled Folate Transporter; 3. Good health

In solid tumors, drug concentrations decrease with distance from blood vessels. However, cellular adaptations accompanying the gradated exposure of cancer cells to drugs are largely unknown. Here, we modeled spatiotemporal changes promoting chemotherapy resistance in breast cancer. Using pairwise cell competition assays at each step during acquisition chemoresistance, reveal an important priming phase that renders previously exposed sublethal refractory dose escalation. Therapy-resistant throughout concentration gradient display higher expression solute carriers SLC38A7 and SLC46A1 elevated intracellular their associated metabolites. Reduced levels diminish proliferative potential cells, these SLCs tumors patients correlates reduced survival. Our work provides mechanistic evidence support dose-intensive treatment modalities for reveals two members SLC family as actionable targets.