Reversible Adaptive Plasticity: Cancer Cell Biology
- Anthony Sandler, MD
- Lina Chakrabarti, PhD
- Priya Srinivasan, PhD
- Clifford Morgan
- Don Devoe, PhD (University of Maryland)
Malignant rhabdoid tumors are extremely aggressive pediatric tumors that arise from the central nervous system, soft tissues, or kidneys. We have recently described a phenomenon of reversible adaptive plasticity (RAP) in neuroblastoma that allows tumor cells to switch their growth patterns between proliferative anchorage dependent (AD) or slow-growing anchorage independent (AI) phenotypes. This cellular plasticity and adaptation enables tumors to evade immune surveillance, survive unfavorable conditions, and/or escape therapy. Each cell type has a distinctive gene expression profile in which key differences define the cell types.
We sought to determine whether RAP is a common feature of other aggressive pediatric solid tumors and if distinct gene expression patterns can predict drug sensitivity. Three human rhabdoid tumor cell lines were tested for phenotypic and molecular changes representing the phenomenon of reversible adaptive plasticity.
Two of the rhabdoid tumor cell lines tested exhibit reversible adaptive plasticity. The line that failed to transition is a chemo-sensitive proliferating cell line. Gene array analysis revealed striking differences between the AD and AI phenotypes of the two cell lines that transition. ID1, ID2, and ID3 genes are differentially expressed and up regulated in the AD phenotype, similar to that of the neuroblastoma cell lines. In addition, the two transitioning cell lines show a marked up regulation of STAT1, ISG15, and IFIT1 genes in the AI phenotype. These genes are characteristic of the interferon-related gene signature for DNA damage resistance (IRDS) observed in several other malignant tumor types. Other differences in gene expression include the MAP kinase signaling pathway, mTOR/PI3K-Akt signaling pathway and genes regulating cell cycle. The AD rhabdoid tumor cell phenotypes are sensitive to chemotherapy while the AI phenotypes are less sensitive or completely resistant to even multi-drug combinations. However, the AI cells are more sensitive to drugs that target the JAK-STAT signaling pathway, a pathway identified by gene array analysis.
Aggressive rhabdoid tumors display reversible adaptive plasticity. The molecular mechanisms underlying RAP in rhabdoid and other highly malignant tumors are critical to their behavior. Defining these pathways will provide insight into developing effective treatment strategies and targets for these highly aggressive tumors.