(6r) Engineering 3D Models of Cancer through Application of Biomaterials and Systems Biology

My lab will use biomaterials and statistical modeling to generate 3D models of cancer in order to guide treatment selection, discover novel targets, and design potential treatment strategies in a high throughput manner. My graduate studies provided me with a strong foundation in using design of experiments multivariate analysis (DOE) to tailor biomaterials in order to instruct cell fate and engineer the immune response. Specifically, I used DOE to engineer the 3D microenvironment in order to optimize the survival, pro-angiogenic, and/or anti-inflammatory potential of mesenchymal stem cells for tissue repair. I carried this expertise into my postdoctoral work developing in vitro models of ovarian cancer, and have added complementary systems biology modeling tools such as partial least squares regression (PLSR) that allow me to analyze paracrine signaling in the metastatic niche. I have recently identified critical components of the pro-tumor macrophage secretome that drive ovarian cancer progression as well as the central signaling pathway that dictates this response. Additionally, by using RNA-Seq in conjunction with an in vitro model of the monocyte-ovarian cancer tumor microenvironment, I have elucidated a non-canonical pathway by which ovarian cancer cells corrupt naïve monocytes towards a pro-tumor phenotype.

My research program will consist of three major focus areas. First, I will develop a personalized predictive model of cancer for pre-clinical evaluation of combinatorial therapies, ultimately incorporating patient cells and accounting for their specific tumor microenvironment. DOE will enable high-throughput screening of multiple bio-inspired input variables such as extracellular matrix components, viscoelastic properties, and growth factor presentation and their combinatorial effects on multiple output variables such as cell proliferation and invasion with the ultimate goal of identifying a hydrogel formulation that elicits the same response in vitro as observed in vivo. This platform can then be combined with patient derived cancer cells and DOE can be used to evaluate the effectiveness of combinatorial therapies. Second, I will identify cross-talk signaling networks between cancer cells, pro-tumor macrophages, and endothelial cells. To accomplish this goal I will combine my postdoctoral work in designing in vitro models of cancer with my doctoral work in vasculogenesis and macrophage polarization in order to construct a tri-culture system of cancer cells, macrophages, and endothelial cells. This will then be used for rapid analysis of cross-talk signaling networks in order to identify treatment strategies to prevent or delay critical processes in cancer metastasis. Finally, I will engineer a delivery vehicle for patient-derived anti-tumor macrophages. Both my doctoral and postdoctoral research projects have focused on modulating macrophage phenotype through presentation of soluble and physical cues; I will build upon this work to design a delivery vehicle for anti-tumor macrophages that maintains the desired phenotype as well as counteracts the pro-tumor capacity of the macrophages already present in the tumor microenvironment.

My lab will focus these tools on the study of cervical cancer, the second leading cause of cancer-related deaths in women aged 20-39. While surgery, chemotherapy, and radiation therapy are effective treatment strategies for early stage cervical cancer, 20% of patients will have recurrent and/or metastatic disease. Immunotherapy is a promising avenue for these patients, as it can disrupt the immune system’s contribution to cancer progression. In tandem, precision medicine enables clinicians to tailor the treatment regimen to the specific characteristics of a tumor. However, a patient’s response to these therapies relies on complex interactions within the tumor microenvironment including the extracellular matrix and surrounding cells. Thus, in order to guide treatment selection and design new treatment strategies the tumor microenvironment must be accounted for in a way that enables high-throughput screening.

Successful Proposals:

Rivkin Center for Ovarian Cancer Scientific Scholar Award; 2017 - Present

American Heart Association Predoctoral Fellowship; 2015 - 2017

Postdoctoral Project: Systems biology approach to interrogate the influence of macrophages on the progression of ovarian cancer

Under supervision of Dr. Pam Kreeger, Biomedical Engineering, University of Wisconsin - Madison

Ph.D. Dissertation: Engineering hydrogel biophysical properties and mesenchymal stem cell microenvironment for tissue repair

Under supervision of Dr. Kent Leach, Biomedical Engineering, University of California, Davis

Education:

Ph.D., Biomedical Engineering, University of California, Davis, 2016

B.S., Chemical and Biological Engineering, University of Wisconsin - Madison, 2010

Publication Highlights: 9 first author papers, 7 co-authored papers, 1 book chapter, 1 conference proceeding. Average impact factor = 5.

Selected Publications (of 16):

1. Carroll MJ, Fogg KC, Patel HA, Krause HB, Mancha AS, Patankar MS, Weisman PS, Barroilhet L, Kreeger PK. Alternatively activated macrophages upregulate mesothelial expression of P-selectin to enhance adhesion of ovarian cancer cells. Cancer Res. 2018 May 8. [Epub ahead of print]
2. Murphy KC, Whitehead J, Zhou D, Ho SS, Leach JK. Engineering fibrin hydrogels to promote the wound healing potential of mesenchymal stem cell spheroids. Acta Biomater. 2017 Dec;64:176-186.
3. Murphy KC, Whitehead J, Falahee P, Zhou D, Simon SI, Leach JK. Multifactorial experimental design to optimize the anti-inflammatory and proangiogenic potential of mesenchymal stem cell spheroids. Stem Cells. 2017 Jun;35(6):1493-1504.
4. Murphy KC, StilhanoRS, Mitra D, Zhou D, Batarni S, Silva EA, Leach JK. Hydrogel biophysical properties instruct co-culture-mediated osteogenic potential. FASEB J.2016 Jan;30(1):477-86.

Teaching Interests:

In college I was heavily involved with Camp Badger, an outreach program that brings in students from underprivileged communities for a one-week summer camp in order to teach them fundamental engineering principles. As a graduate student I served as a teaching assistant as well as a teaching associate for 10 different courses in four departments, including chemical engineering. As a teaching associate for transport phenomena as well as chemical kinetics and reactor design I prepared and gave lectures as well as lead discussions and held office hours.

From my B.S. in chemical engineering at UW-Madison, I am comfortable with a full chemical engineering curriculum; however, based on my research and teaching experiences I would most enjoy teaching transport phenomena, chemical kinetics and reactor design, and process synthesis at the undergraduate level. Additionally, I would enjoy teaching or developing graduate coursework in biomaterials, design of experiments for material and process design, and stem cell engineering.