Metastasis is responsible for 90% of cancer associated mortality indicating the need for new therapies targeted specifically toward preventing and/or eliminating metastasis. Cells originating from breast tumors display distinct organotropic metastasis patterns and hone specifically to lung, brain, or bone. Once a distant tissue is infiltrated, these cells often lay dormant for many years, or even decades, before reverting to an actively proliferating state. These dormant micrometastases composed of single cells, or small cell clusters, are highly resistant to conventional chemotherapies that only effectively treat actively proliferating cells. While animal models have traditionally been used for therapeutic screening, resolution limitations of in vivo imaging modalities make it difficult to quantify the effectiveness of new therapies targeted toward preventing extravasation or eliminating dormant micrometastases. To circumvent this limitation, we propose the generation of a vascularized in vitro metastasis model to induce organotropic extravasation and formation of dormant metastases. We will utilize our expertise in the development of biochemically and mechanically tunable synthetic hydrogel constructs to generate tissue-specific environments that allow for cancer cell infiltration via extravasation and that induce a dormant state in extravasated cells. We have recently developed an image-guided, laser-based hydrogel degradation technique that allows for fabrication of 3D microfluidic networks that accurately recapitulate the complex, dense architecture of in vivo vasculature in vitro. We will combine this new technology with our expertise in the fabrication of engineered microenvironments to generate a 3D vascularized in vitro model composed of organ-specific microtissues that recapitulate the biochemical, mechanical, and hemodynamic properties of brain, lung, and bone tissue to generate an organotropic breast cancer model that induces dormancy upon cancer cell infiltration. Through this funding mechanism we will organize our research to achieve the following objectives: (i) generate organ-specific tissue constructs that recapitulate the mechanical, chemical, and hemodynamic properties of brain, lung, and bone tissue that allow for infiltration and induce dormancy in highly metastatic cancer cells, (ii) demonstrate the ability to induce organotropic extravasation of breast cancer cells with genetic signatures known to induce metastasis specifically to brain, lung, or bone, and (iii) demonstrate the ability to quantitatively monitor extravasation, infiltration, and dormancy. This in vitro device to model organ- specific formation of dormant metastases could provide significant insight into the environmental mechanisms that govern organotropic metastasis, formation of dormant metastases, and aid the development of new therapeutics targeted specifically toward halting extravasation or eliminating dormant micrometastases.
Metastasis is responsible for 90% of cancer associated mortality indicating the need for new therapeutics that effectively prevent extravasation or eliminate chemotherapeutic resistant, dormant micrometastases. Current in vivo imaging modalities do not possess the resolution needed to monitor single cells or small cell clusters undergoing extravasation or that have formed micrometastases making animal models difficult to implement for screening of metastasis-specific therapeutics. To overcome this limitation, we will develop an in vitro organotropic metastasis model to induce the formation of dormant micrometastases which can be implemented to develop and test metastasis-specific therapeutics targeted at preventing extravasation or toward eliminating dormant micrometastases.
| Pradhan, Shantanu; Keller, Keely A; Sperduto, John L et al. (2017) Fundamentals of Laser-Based Hydrogel Degradation and Applications in Cell and Tissue Engineering. Adv Healthc Mater 6: |
