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

Yannick Audet-Delage1, Catherine St-Louis1, Lucía Minarrieta1

  • 1Ottawa Institute of Systems Biology and Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.

Cell Reports
|October 4, 2023
PubMed

Insights

Chemotherapy resistance in solid tumors involves a priming phase where cancer cells adapt to low drug doses. This adaptation, linked to SLC38A7 and SLC46A1 expression, impacts treatment effectiveness and patient survival.

Area of Science:

  • Oncology
  • Cancer Biology
  • Pharmacology

Background:

  • Drug concentrations in solid tumors decrease with distance from blood vessels, creating a gradient.
  • Cellular adaptations to this gradient and their role in chemotherapy resistance are not well understood.

Purpose of the Study:

  • To model and investigate the spatiotemporal dynamics of chemotherapy resistance acquisition in breast cancer.
  • To identify cellular mechanisms and molecular targets associated with drug resistance in solid tumors.

Main Methods:

  • Utilized pairwise cell competition assays to study chemoresistance development across a drug concentration gradient.
  • Analyzed gene expression of solute carriers (SLCs) and their metabolite levels in resistant cancer cells.
  • Correlated SLC expression in patient breast tumors with clinical outcomes.

Main Results:

  • Identified a critical 'priming phase' where prior exposure to sublethal drug concentrations induces resistance to dose escalation.
  • Therapy-resistant cells exhibited increased expression of solute carriers SLC38A7 and SLC46A1 and elevated metabolite levels.
  • Reduced SLC38A7/SLC46A1 levels impaired cancer cell proliferation, while high expression correlated with poorer patient survival.

Conclusions:

  • Mechanistic insights support dose-intensive chemotherapy for solid tumors.
  • SLC38A7 and SLC46A1 represent potential therapeutic targets for overcoming chemotherapy resistance.
Keywords:
CP: CancerCP: Metabolismanthracyclinesbreast cancercancer metabolismchemotherapy resistancemetabolomicssolute carriers

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