Project Engineering the premetastatic niche Program DUIRI - Discovery Undergraduate Interdisciplinary Research Internship Term Summer 2025 Status Accepted Research Area Biomedical engineering, cancer biology, mechanobiology, tissue engineering, and imaging Description Metastasis is the single greatest driver of cancer-related mortalities, regardless of the tumor’s tissue of origin. This is particularly true for breast cancer, where the five-year survival rate is exceptional if the disease remains local. However, once breast cancer has metastasized, patient survival drops almost 75%. A defining hallmark of metastasis is the ability of primary tumor cells to modulate the local environment to facilitate tissue invasion. These microenvironmental cues can elicit reciprocal phenotypic transitions, giving rise to heterogenous populations of tumor cells, facilitating metastatic initiation and drug resistance. Additionally, tumor cells can also modify the microenvironment of future metastatic sites well before they colonize these tissues. Key features of these premetastatic niches (PMN), including a unique extracellular matrix (ECM) and cellular composition, help facilitate crucial steps of the metastatic cascade. Given the complexities of these tumor-host interactions, there is a critical need to engineer in vitro platforms to study PMN formation. Use of these controlled model systems will aid in ability to devise strategies capable of altering the soil to restrict growth of the cancerous seeds. Extracellular vesicles (EVs) play an important and newly-identified role in establishing the PMN. It has recently been observed that in murine models, pre-treatment with tumor derived EVs can not only enhance metastasis, but they also influence which tissues are colonized through an integrin-mediated pathway. Despite these advances, there remain fundamental gaps in understanding the mechanism through which the PMN facilitates metastatic seeding, how the PMN gives rise to heterogenous populations of cells capable of colonizing the newly invaded tissue, and how the components within the niche reduce therapeutic efficacy. To address these gaps, we have established a 3D culture model consisting of human pulmonary fibroblasts that can be pretreated with EVs prior to coculture with tumor cells. Using this reductionist model of the PMN, we have demonstrated that EVs produced by metastatic tumor cells enhance colonization. Furthermore, we have demonstrated the matrix modifying enzyme transglutaminase 2 (TG2) is loaded onto EVs and that genetic deletion of TG2 drastically inhibits the metastasis of mammary tumors and prevents the ability of EVs to promote pulmonary tumor formation. Given these findings, we seek to address the hypothesis that disrupting premetastatic niche formation can be used to mitigate metastatic outgrowth and improve patient response to therapy. Supervisor Luis Solorio Mentor Madison Mckensi Howard Type of work required Students will learn to use 3D tissue culture platforms, perform histology, evalaute cell migration, immunofluorescence, and evalaute matrix remodeling events using proteomics and noncanonical amino acids. Websites https://soloriolab.wixsite.com/tmet Qualifications GPA above 3.0, biochemistry or equivalent course work, previous lab experience is preferred, and strong communication skills are a plus. Credit Hours 0 Weekly Hours 40 (estimated)