The Tumor Microenvironment (TM) Program at UW-Madison capitalizes on the involvement of many outstanding investigators whose research is focused on cell-ECM interactions, ECM structure and function, tumor cell migration and invasion, cell-cell adhesion, paracrine signaling between tumor and stromal cells, immune cell trafficking into tumors, tumor angiogenesis, metabolism, and development of in vitro models.
The UWCCC Tumor Microenvironment program encompasses research focused on how the host-tissue environment impacts tumor formation and progression. This research includes investigations into cell-ECM interactions, ECM structure and function, tumor cell migration and invasion, cell-cell adhesion, paracrine signaling between tumor and stromal cells, immune cell trafficking into tumors, tumor angiogenesis, and metabolism.
The overarching goal of the TM program is to understand how the interactions between the diverse elements of the tumor microenvironment affect tumor formation, progression, and response to therapy.
Thematic Aim 1: Identify elements in the microenvironment that accompany tumor initiation and progression. The TM program has a strong history of innovation and impact in this area, with a particular focus on the role of the extracellular matrix (ECM) in cancer initiation, progression and response to therapy. TM members have ongoing studies analyzing the impact of changes in ECM composition and structure on metastasis and therapy response, as well as examining how changes in the ECM could be used as biomarkers.
Thematic Aim 2: Develop and apply systems that manipulate and probe the impact of the tumor microenvironment. To understand the complex microenvironment, it is necessary to have controlled systems where the individual variables can be manipulated to study the outcome on phenotypic events associated with tumor progression (e.g., proliferation, migration). Collaborative teams within TM and between TM and the other programs are developing and utilizing these systems to identify mechanisms regulating tumor progression and response to therapy.
Thematic Aim 3: Analyze the interactions between different elements of the tumor microenvironment. Understanding the complexity of the interactions between the tumor cell and other cell types in the microenvironment (e.g., immune cells, fibroblasts, endothelial cells) will help identify new mechanisms to slow or stop cancer progression. Importantly, these interactions go beyond the bi-directional communication between the tumor cell and one cell type, and extend to multi-cellular interactions that affect processes such as metastasis, proliferation, and response to therapy.
Select Recent Accomplishments
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The extracellular matrix is an active participant in cancer, influencing initiation, progression, and response to therapy. A long-standing focus and strength of the TM program has been to understand both the structural and signaling roles of the matrix in cancer.
- Campagnola, and Patankar (DT) identified collagen structure as a prognostic biomarker in ovarian cancer with 83-91% accuracy rate which is superior to current clinical performance
- Cryns examined the role of matrix detachment in regulation extracellular-signal regulated kinase (ERK) activity. ERK inhibition can mimic matrix detachment to manipulate circulating tumor cells
- Keely and Schuler (DT) examined how increased collagen density impacts breast tumor cell response to prolactin demonstrating that prolactin treatment resulted in increased proliferation, invasion, and cross-talk with estrogen when the tumor cells were cultured in dense collagen
The integration of engineers into the UWCCC and particularly the TM program is a strength that has allowed us to be a leader in the application of engineering approaches to biomedical research broadly and cancer research specifically.
- Campagnola, Eliceiri, and Patankar (DT) use nanofabrication to create models of ECM at nano and micro scale
- Beebe developed innovative models of tissue structure at micro and macro scales to more accurately identify the influence of interventions
- Masters used a novel biomaterial to independently tune ECM stiffness while concentration is held constant
- Wilke, Beebe, and Burkard (GEM) designed implantable device that allows for drug diffusion and evaluation in the native environment for more effective treatment selection
- Skala developed new methods in microscopy to monitor cell-level metabolism in tumors in vivo.
Recent advancements in understanding the immune system has led to discoveries in the ways tumor cells restrict an anti-tumor immune response through the immune checkpoint, which has led to a host of new therapeutic agents. Moreover, the host immune system can be co-opted by the tumor to serve a protumorigenic role.
- Rakhmilevich and Sondel (DT) investigated optimal immunotherapies for multiple myeloma to explore the role of immune cells in therapeutic response
- Eliceiri, and Keely advanced the field’s ability to identify and study immune components through non-invasive autofluorescence imaging to quantify both tumor and immune cell response in vivo
- Kreeger and Patankar (DT) developed a novel co-culture system to examine paracrine interactions in order to better understand how macrophages impact tumor cells
- Huttenlocher used zebrafish model to further explore tumor regulation of neutrophil recruitment and quantify the earliest stages of macrophage infiltration
- Keely, Wilke, and Burkard (GEM) developed trial for treating tumors in a dense collagen environment