Metastasis is the stage of cancer progression in which the disease becomes lethal, and clinicians are unable to determine when metastases have occurred until the cells have colonized one or more distal sites and subsequently affected the functioning of that tissue. The sampling of blood for circulating tumor cells or for the presence biomarkers for metastasis has many challenges for effectively detecting metastases. We propose a transformative approach in which a site is defined using a biomaterial implant that will induce homing and colonization of circulating metastatic cells. Furthermore, we hypothesize that optical imaging techniques can be employed that would enable non-invasive detection of colonization. This system would provide a step toward initiating therapies at early stages of metastatic disease, and the implant could be retrieved for cellular analysis and determination of a therapy based on the biology of the metastatic cells. The first step in these studies is to identify the signals within the pre-metastatic niche that promotes metastatic cell homing and colonization. The factors secreted by the "niche" cells will be identified through the combination of a cellular array for the high throughput analysis of TF activity, and proteomics analysis of culture media. The cell array will identify the key pathways within metastatic cells responsible fo homing and colonization, and the proteomics analysis will identify the numerous factors secreted by the niche cells. This combination of activated pathways and available factors is anticipated to identify the key factors driving the phenotype, which can be employed in Aim 2 that aims to design biomaterial implants to promote in vivo homing and colonization of metastatic cancer cells. These implants, which building upon techniques from regenerative medicine, will deliver cells associated with the pre-metastatic niche and/or deliver gene therapy vectors encoding for factors that either recruit cells associated with the pre-metastatic niche, which can locally produce factors that recruit metastatic cells. Additionally, vectors encoding for factors that directly recruit metastatic cells can be delivered. Taken together, these studies will identify environments that promote metastatic cell homing and colonization in vivo, which may provide targets for therapeutic intervention. Finally, non-invasive optical imaging techniques will be developed to detect colonization of the implant by metastatic cells, using techniques that could be readily translated to the clinic. Taken together, these implants have the potential to revolutionize cancer treatment by providing for early detection of metastatic disease, thereby allowing for early interventions.
Cancer is the second leading cause of death worldwide, with most cancer-related deaths resulting from metastasis of cells from the primary tumor. Our transformative proposal is aimed at detecting metastasis at the earliest stages, which could allow for life-preserving interventions. For this early detection, we propose to develop an implant that would recruit metastatic cancer cells and a sensor to identify when cancer cells have colonized the implant.
|Spicer, Graham L C; Azarin, Samira M; Yi, Ji et al. (2016) Detection of extracellular matrix modification in cancer models with inverse spectroscopic optical coherence tomography. Phys Med Biol 61:6892-6904|
|Dumont, Courtney M; Margul, Daniel J; Shea, Lonnie D (2016) Tissue Engineering Approaches to Modulate the Inflammatory Milieu following Spinal Cord Injury. Cells Tissues Organs 202:52-66|
|Margul, Daniel J; Park, Jonghyuck; Boehler, Ryan M et al. (2016) Reducing neuroinflammation by delivery of IL-10 encoding lentivirus from multiple-channel bridges. Bioeng Transl Med 1:136-148|
|Aguado, Brian A; Caffe, Jordan R; Nanavati, Dhaval et al. (2016) Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche. Acta Biomater 33:13-24|
|Rao, Shreyas S; Bushnell, Grace G; Azarin, Samira M et al. (2016) Enhanced Survival with Implantable Scaffolds That Capture Metastatic Breast Cancer Cells In Vivo. Cancer Res 76:5209-18|
|Liu, Jeffrey M H; Zhang, Jesse; Zhang, Xiaomin et al. (2016) Transforming growth factor-beta 1 delivery from microporous scaffolds decreases inflammation post-implant and enhances function of transplanted islets. Biomaterials 80:11-9|
|Azarin, Samira M; Yi, Ji; Gower, Robert M et al. (2015) In vivo capture and label-free detection of early metastatic cells. Nat Commun 6:8094|
|Dumont, Courtney M; Park, Jonghyuck; Shea, Lonnie D (2015) Controlled release strategies for modulating immune responses to promote tissue regeneration. J Control Release 219:155-66|
|Yi, Ji; Stypula-Cyrus, Yolanda; Blaha, Catherine S et al. (2015) Fractal Characterization of Chromatin Decompaction in Live Cells. Biophys J 109:2218-26|
|Thomas, Aline M; Palma, Jaime L; Shea, Lonnie D (2015) Sponge-mediated lentivirus delivery to acute and chronic spinal cord injuries. J Control Release 204:1-10|
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