The tumor microenvironment plays a crucial role in tumor development and progression. Tumors alter the topography and molecular composition of stromal extracellular matrix (ECM) by regulation of fibroblastic stromal cells during tumor development. These physical and biochemical alterations of the stroma affect the properties of naive stromal cells to become activated and fuel stromal activation thus promoting cancer cell progression. The vital interplay between tumor and stroma means that, in principle, it is possible to target signaling pathways that regulate tumor-induced stroma activation and thereby contain tumorigenesis. We have developed 3D in vitro and an ex vivo systems comprising cells plated in 3D in matrices derived from stromal fibroblasts or in decellularized tumorigenic tissue ECMs. Using these systems, we have not only observed that stromal matrices are modified as the tumor develops but that tumor matrices are both necessary and sufficient to induce normal fibroblasts to display properties characteristic of tumor-associated fibroblasts. In the past we showed that alterations in integrin-dependent signaling pathways are critical to the development of tumor-promoting stroma and that tumor cell invasion can be repressed by targeting fundamental stroma components. In collaboration with a team of clinical researchers focused on kidney cancer, we have developed extensive resources to dissect stromal-tumor interactions in this disease. Preliminary results rendered: a proteomic signature that has defined a group of proteins including lysyl oxidase (LOX), and periostin as specifically upregulated in tumor-associated ECM, and identified palladin stromal expression as highly predictive of tumor prognosis in renal cancer. In this study we propose to: 1. Test the hypothesis that specific structural and biochemical components of the tumor-associated ECM collaborate to induce a phenotypic switch in naive fibroblasts. 2. Establish the role for palladin in the phenotypic switch regulated by specific integrin crosstalk induced by tumor-associated but not normal ECM. 3. Assess the clinical importance of stromal activation in human renal cell carcinoma (RCC).
Results stemming from this study will facilitate uncovering some of the mechanisms responsible for the tumor fueling vicious cycle which maintains stroma activation and in turn incites tumor progression. The study will emphasize the clinical relevance of assessing the progression of mesenchymal stroma, and it could reveal possible targets to prevent stroma progression and consequently stall tumorigenesis.
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