"how cancer cell-ECM interaction stimulates cancer-promoting phenotypes"
Investigation of cancer cell-ECM interaction developing tumor with in vitro ECM models
Cancer cells actively modify tumor microenvironment (TME) for tumor progression. Extracellular matrix (ECM), a major component of TME supporting embedded cells physically in the tissue, undergoes re-organization by cancer cells. The reorganized ECM reciprocally regulates cancer-related phenotypes such as invasive migration facilitating tumor progression. This suggests that the elucidation of cancer cell-ECM interaction can provide important cues to understanding cancer promoting mechanism and thus improving cancer treatment. Therefore, as leveraging in vitro ECM models wish nanofabricated surfaces or 3D model, our lab aims to address how cancer cell-ECM interaction stimulates cancer-promoting phenotypes such as invasive cell migration and heterogeneous cell-cell interaction synergically with oncogenic alteration.
1. Engagement of ECM reorganization in the interaction between cancer cells and other neighboring cells in TME promoting tumor development
ECM reorganization is a pathologically common feature in TME, e.g., the locally degraded ECM on the basement membrane and 2) the aligned ECM in the interstitial stroma. In addition to embedded cancer cells, other cells, e.g., immune cells consisting of TME adapt themselves to the reorganized ECM. However, the research on how their adaptation influences tumor progression is strikingly sparse because of the dearth of easily accessible experimental tools to model the complicated interaction among cancer cells, other cells and ECM in TME. Therefore, we will develop in vitro models with nanofabricated surfaces and co-culture systems simplifying the complicated nature of the TME, but well replicating its pathophysiologically critical features. We expect that the research with the innovative in vitro models combined with systems biology approaches will explain the contribution of ECM reorganization to tumor progression via modulating the interaction of other neighboring cells such as immune cells with cancer cells and provide the insights into the potentials of cancer therapy targeting TME.
2. Identify signaling molecules regulating cancer cell-ECM interaction in TME that promotes metastasis through phenotypic filtering
During cancer invasion for metastasis, cancer cells encounter reorganized ECM by cancer cell-ECM interaction. Recent findings suggest that cancer cells in the proposed in vitro models approximating the effect of reorganized ECM in TME exhibit more in vivo-like cell phenotypes. Particularly, a limited number of cells with higher metastatic potentials among the genetically or phenotypically heterogeneous cancer cells respond more sensitively to the reorganized ECM than other cells presumably causing distinctive phenotypes, e.g., A) directional migration guided by topographical gradient (topotaxis) and B) epithelial-mesenchymal transition induced by topographical cues from ECM. Here, we propose the identification of key molecules to regulate metastasis through the phenotypic filtering with the respect to metastasis-related phenotypic outcomes resulting from cancer cell-ECM interaction. The proposed filtering will allow 1) identifying the signatures regulating metastasis as pinpointing the genetic mutations exclusively found in filtered sub-population of cells and 2) unraveling underlying mechanism to modulate metastasis as contrasting the genome/epigenome/transcriptome of filtered sub-populations. Further application of the phenotypic filtering to specific tumor samples from the patients can assist in better-personalized tumor diagnostics and prognostics.
