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Emerging studies increasingly suggest an active role for the primary tumor-mediated pre-metastatic niche at the secondary organ in supporting future cancer cell infiltration. However, owing to the limited set of tools that can map subtle differences in molecular mediators in organ-specific microenvironments, etiology of such pre-metastatic niches remains poorly understood. Novel non-perturbative tools that can provide quantitative insights into subtle changes in biochemical composition of secondary sites prior to morphological manifestations are urgently needed. To address this unmet need, we have developed an approach to detect pre-metastatic changes in the lung microenvironment, in response to primary breast tumors, using a combination of metastatic mouse models, Raman spectroscopy and multivariate analysis. Specifically, we employed orthotopic breast cancer xenografts comprised of high (MDA-MB-231) and low (MCF-7) metastatic tdTomato fluorescent protein expressing cells and performed label-free Raman spectroscopic mapping to record the molecular content of pre-metastatic lungs. Our study reveals discriminative Raman features, characteristic of collageneous stroma as well as proteoglycans, that uniquely identify the metastatic potential of primary tumor based on the compositional changes in their lungs. The spectroscopic findings are in agreement with Masson’s trichrome staining observations and gene expression analysis of microarray data of pre-metastatic lung samples from mice harboring breast tumor xenografts of varying metastatic potential. The presented data are both unique and complementary to that acquired using conventional analytical tools such as downstream genomic tests and fluorescence-tagged cell tracking. Overall, our findings create a new landscape for spectroscopic monitoring of pre-metastatic niche by uncovering discriminative stromal spectroscopic features in secondary sites.
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