Study the Primary and Distal Metastatic Microenvironments through Ddr1 Affect Therapeutic Strategy of Bladder Cancer(1/2)

Rationale: Metastatic progression of the primary tumor accounts for the majority of cancer deaths. While the mechanisms of the metastatic cascade are rather well studied, identification of targets to eradicate/manage metastases remain a major clinical challenge and is the goal of this proposal. Previous studies in bladder urothelial carcinomas have investigated the mechanistic contribution of intrinsic tumor cell properties that promotes metastasis. However, the functional significance of the tumor microenvironment is currently not well characterized and research in this area is limited, due to the deficiency of banked patient tissues (at the distal metastatic sites) and limited metastatic models available. Hence, the current proposal is significant by developing one-of-a-kind patient-derived metastatic models for bladder carcinomas to study the impact of tumor and metastatic collagen microenvironments for the therapeutic intervention via a collagen receptor-DDR1. Preliminary results: Our preliminary results from in vitro and in vivo study suggested the primary and distal metastatic collagen microenvironments can modulate DDR1 tyrosine phosphorylation status. These results include the following: (1) the phosphorylation of DDR1 at Y792 differentially responds to distinct exogenous collagen types (COL1 and COL3) treatment. (2) Matched primary tumor and distal lung metastases from the same in vivo bladder PDX animal model showed that in the COL1-rich primary tumor site, cancer cells expressed higher phospho-Y792 levels, whereas lower phospho-Y792 expression in COL3-rich lung niche. (3) Lung niche specific ASMC-conditioned medium treatment induced cell morphology change and a markedly reduced in Y792 phosphorylation levels. Furthermore, (4) we had performed a SH2 domain array and identified some candidate downstream effectors that bind to pY792 site. (5) To investigate how niche-specific cells impact tumor cells, we had isolated and cultured human cancer-derived fibroblasts (CAF) for the future experiments. Hypothesis: Our preliminary results revealed that DDR1 can respond to different collagen types stimulation. We hypothesize that distinct collagen components at the primary tumor and distal lung metastatic microenvironments can differentially impact downstream collagen receptor signaling; therefore, that will lead to primary tumors and metastatic foci in patients respond differentially to therapies. Specific Aims: To address our hypothesis, three aims will be conducted. Aim 1: To examine whether niche-specific collagens differentially regulate DDR1 tyrosine phosphorylation sites. Aim 2: To investigate the downstream effectors of DDR1-specific phosphorylation sites and their biological function. Aim 3: To examine whether therapeutically target distinct DDR1-effectors can as new approaches to target metastatic foci.Novelty and application: Greater than 90% of all cancer deaths result from distal metastasis. Our research, using bladder cancers as a model, will provide new understanding to why primary tumors and metastatic foci in patients respond differentially to conventional (e.g. chemotherapy) and targeted therapies. This information generated through this proposal will has the potential to transform the current clinical therapeutic strategy for most cancer patients with metastatic issue. Moreover, we expected the selected downstream effectors will be potentially served as diagnostic, prognostic biomarkers for bladder cancer patients, and the interactions among the selected effectors and their regulatory networks will shed new light on bladder tumor targeted therapies.