Heterogeneity in cancer is an observed fact, both genetically and phenotypically. Cell-to-cell variation is seen in all aspects of cancer, from early development to invasion and subsequent metastasis. This heterogeneity is also at the heart of why many cancer treatments fail, as it facilitates the emergence of drug resistance. The complex spatial and temporal process by which tumors initiate, grow and evolve is a major focus of the oncology community and one that requires the integration of multiple disciplines. Tumor heterogeneity at the tissue scale is largely due to ecological variations in
terms of the tumor habitat driven by spatially heterogeneous vascularity, which is
readily observed on cross sectional imaging. Molecular techniques have
historically averaged genomic signals from large numbers of cells obtained in a
single biopsy site, thus smoothing and potentially hiding underlying spatial
variations. The complex dialogue between tumor cells and
environment that produces intra- and inter-tumoral heterogeneity is
fundamentally governed by Darwinian dynamics. That is, local microenvironmental conditions select phenotypic clones that are best adapted to
survive and proliferate and, conversely, the phenotypic properties of the cells affect the
environmental properties. While these complex interactions have enormous
clinical implications because they promote resistance to therapy, the dynamics
are impossible to fully capture via experimentation alone. Here we present an integrated theoretical/experimental approach to develop dynamical models of the complex multiscale interactions that manifest as temporal and spatial heterogeneity in cancers and ultimately govern tumor response and resistance to therapy. Specifically, we examine the impact of microenvironmental modulation on cancer evolution both in silico, using a hybrid multiscale mathematical model, and in vivo, using three different spontaneous murine cancers. These models allow the tumor to be steered into a less invasive pathway through the application of small but selective biological force. Our long term goal is explicitly translational as we focus our integrated approach on an emerging cancer treatment paradigm that actively harnesses evolutionary dynamics to improve patient outcomes.

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