A tumor-mesenchymal in vitro model of Hedgehog signaling in triple negative breas

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DESCRIPTION (provided by applicant): The PI holds a tenure track faculty position at the University of Puerto Rico in Mayaguez (UPRM) since January 2013 and is a member (adjunct assistant investigator) of the University of Puerto Rico Comprehensive Cancer Center (UPRCCC). Through her research career in the biomedical engineering field, she gained expertise in developing microfluidic devices and nanoparticle technologies for the study of cell signaling networks and therapies relevant to the progression of cancer. The PI's long term goal is to become an independent investigator in the cancer research field and a leader in the development of in vitro tumor microenvironment models that advance the study of processes that lead to cancer progression and therapy resistance. As a young investigator in the biomedical engineering field, the PI wants to fill critical knowledge gaps in the area of the tumor microenvironment and clinical therapeutic approaches to contribute to the broader cancer research field as an independent research professor. To continue progress towards becoming an independent cancer researcher, the PI, mentor and co-mentor developed a comprehensive career training plan to expand the PI's knowledge in breast tissue physiology, tumor microenvironment and therapeutic strategies. The career training plan involves research studies of tumor microenvironment, development of collaborations among clinical and engineering researchers at the UPRCCC, guided visits to the cancer clinic and the establishment of an on-campus cancer niche composed by clinicians, biology and engineering researchers. Environment: The UPR is a minority research institution composed by 11 campuses including Medical Sciences campus and UPRCCC. As a full-time faculty member of the UPRM, the PI has the opportunity to participate in multi-disciplinary professional development opportunities, biomedical research seminars and interact with a pool of biomedical researchers supported through various research centers at UPRM and other campuses. As part of the PI's recruitment package, the UPRM provides academic release time, stipend for graduate students, a private office space, a research laboratory, materials and access to shared biomedical laboratory facilities. As member of the UPRCCC, the PI has access to research activities (conferences/symposiums, meeting) and use of facilities/equipment in the UPRCCC. The UPRCCC hosts seminars, research meetings and workshops which are focused on advances in cancer research and therapeutic approaches. Researchers at the UPRCCC have the opportunity to interact with a professional network composed by researchers and clinicians at local and partner clinical centers in the cancer field. Research: Triple negative breast cancer (TNBC) is a clinical therapeutic challenge due the lack of responsiveness to standard adjuvant chemotherapy. Hedgehog (Hh) Recent studies show that signaling correlates with reduced survival rates in TNBC patients and pharmacological inhibition significantly reduces growth and invasion suggesting a potential therapeutic value for Hh inhibitors. The main cellular target of Hh inhibitors is the adjacent mesenchyme which has shown to promote tumor growth via a paracrine interaction. The source of mesenchymal cells in breast cancer tissues is unknown, with myo-differentiated fibroblasts, mesenchymal stem cells, and tumor cells that undergo epithelial-mesenchymal transition as main alternatives. There is a gap in knowledge regarding the role of mesenchymal cells derived from various sources in the development, progression and response to therapy of TNBC and other cancers. The objective in this project is to develop a tumor-mesenchymal in vitro model to evaluate the role of active Hh signaling in mesenchymal cells from different sources on the progression of TNBC. We hypothesized that active Hh signaling in the mesenchyme promotes tumor growth and that this effect is dependent on the source of mesenchymal cells. This research is based upon our preliminary data and work of others showing co- expression of Hh signaling target genes and mesenchymal markers in TNBC and increase in tumor cell growth through active Hh signaling in the adjacent mesenchyme. To address our hypothesis the following specific aims are proposed: Specific Aim 1. Determine the influence of Hh signaling in mesenchymal cells derived from different sources in the expansion TNBC cells and Specific Aim 2. Establish a gene signature composed by mesenchymal and Hh signaling markers to identify disease stage and potential patient candidates for Hh inhibitors. In aim 1, we will develop a tumor-mesenchymal in vitro model combining up to 3 mesenchymal cell types with active Hh signaling in a multi-compartment microplatform. In aim 2, we will develop a preliminary Hh-mesenchymal gene signature using public gene banks of TNBC to establish correlation among breast cancer stage for validation in tumor tissue samples. The outcome of the studies proposed here will influence the development of novel therapeutic approaches directed at the tumor microenvironment as a complement to conventional therapies targeting the tumor cells. Overall, the proposed approach will significantly impact both the cancer biology and translational medicine field.