Cell types or cell states? An investigation of adrenergic and mesenchymal cell phenotypes in neuroblastoma
Anuraag Bukkuri,
Stina Andersson,
Marina S. Mazariegos,
Joel S. Brown,
Emma U. Hammarlund,
Sofie Mohlin
Affiliations
Anuraag Bukkuri
University of Pittsburgh School of Medicine, Department of Computational and Systems Biology, Pittsburgh, PA, USA; The Center for Philosophy of Science at the University of Pittsburgh, Pittsburgh, PA, USA; Cancer Biology and Evolution Program and Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA; Department of Experimental Sciences, Lund University, Lund, Sweden; Corresponding author
Stina Andersson
Division of Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Lund University Cancer Center, Lund University, Lund, Sweden
Marina S. Mazariegos
Division of Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Lund University Cancer Center, Lund University, Lund, Sweden
Joel S. Brown
Cancer Biology and Evolution Program and Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA
Emma U. Hammarlund
Department of Experimental Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Lund University Cancer Center, Lund University, Lund, Sweden
Sofie Mohlin
Division of Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Lund University Cancer Center, Lund University, Lund, Sweden; Corresponding author
Summary: Neuroblastoma exhibits two cellular phenotypes: therapy-sensitive adrenergic (ADRN) and therapy-resistant mesenchymal (MES). To understand treatment response, it is important to elucidate how these phenotypes impact the dynamics of cancer cell populations and whether they represent distinct cell types or dynamic cell states. Here, we use an integrated experimental and mathematical modeling approach. We experimentally measure the fractions of ADRN and MES phenotypes under baseline (untreated) conditions and under repeated treatment cycles. We develop evolutionary game theoretic models predicting how the populations would respond if ADRN and MES phenotypes (1) are distinct cell types or (2) represent dynamic cell states and fit these models to the experimental data. We find that, although cells may undergo an ADRN to MES phenotypic switch under treatment, the best-fit model sees ADRN and MES as distinct cell types. Differential proliferation and survival of these two cell types, and not cell-state switching, drive therapeutic response.
