The applicants will use multiphoton excited (MPE) photochemistry to fabricate models of the ovarian extracellular matrix (ECM) as platforms to study early stages of ovarian carcinoma. The ECMs will consist of crosslinked basal lamina and stromal layers, where each will be comprised of the respective predominant protein composition in vivo. As these nano/microstructured models will simulate the crosslinked fibrillar structure of the native ECM, they will be significantly more biomimetic than those reported previously (e.g. culture coatings and flow chambers), which are limited by the lack of concurrent appropriate topographic and biochemical structure. These devices will allow the testing of pathway activity not immediately possible in human subjects or even animal models. these models will be used to investigate the cellular surface dynamics (Aim 1) and ECM remodeling of the ovarian stroma (Aim 2) that both may occur in early carcinogenesis and may underlie disease progression. To this end, they will compare the functional response of ovarian tumor cells in terms of differentiation, migration, adhesion strength, integrin expression, proliferation as well as the ability to invade and remodel the ECM. They will specifically modulate the expression of metalloproteinases (MMPs) implicated in ECM remodeling and metastasis via stimulation with cytokines and growth factors. These experiments will reveal the biochemical and morphological factors operative in carcinogenesis and metastasis.
