(4bq) Investigating the Tumor Microenvironment through State-of-the-Art DNA-Based Technology

My research experience has been characterized by applying interdisciplinary and, especially, innovative engineering approaches to advance scientific discovery. From clinical sample-oriented research in my doctoral work to the intricate systems to perform high-throughput biological studies I created as a postdoctoral scholar, I have developed and utilized state-of-the-art technologies and materials toward clinical applications and biological research. As a researcher operating at the interface of biology and engineering, I have a strong and extensive track record of creative approaches to scientific challenges. My overarching career objective is to build an interdisciplinary and diverse community of researchers to advance and innovate the technology we use to study and monitor cancer.

Research Interests: My diverse research interests are united by my goal of applying engineering principles to pressing medical challenges. As an NSF graduate research fellow at the University of Michigan, Ann Arbor, I spanned disciplines by applying my chemical engineering knowledge and skills to isolate rare circulating tumor cells (CTCs) from patient blood samples (Fig. 1a). I used the innovative, highly sensitive, nanomaterial-based graphene oxide (GO) Chip to isolate and explore the role of CTCs in the progression of genitourinary cancers based on not only CTC counts, but also metrics related to EGFR expression, CTC clusters, RNA expression levels¹, and protein-level EGFR expression². In parallel to pursuing these clinically-oriented projects, I also worked to advance the next-generation GO Chip technology by using a tunable copolymer to release captured CTCs efficiently³. As an F32 postdoctoral fellow at UC Berkeley, I am currently developing, optimizing, and employing a novel biopatterning technology⁴, which has wide applications ranging from nanoparticle patterning⁵ to viral detection⁶, to probe the intricacies of cancer as a highly interactive and malleable disease. Cancer cells can travel to distant locations and remain dormant for years before disrupting the health of the patient. However, only 50% of patients with disseminated tumor cells (DTCs) ultimately develop overt metastases, with only 1% of DTCs progressing into macrometastases. Understanding the mechanism behind their switch out of dormancy is of critical importance to clinicians and researchers hoping to predict disease trajectory. In this regard, I am harnessing the power of DNA-directed patterning to investigate those single-cell and systems-level interactions that are present in the tumor microenvironment in the bone marrow that influence the fate of DTC. By investigating at the interactions between prostate cancer cells and the cells of the bone-marrow tumor microenvironment (e.g. osteoclasts, osteoblasts/osteocytes, and endothelial cells) (Fig. 1b), I can tease out those that influence disease progression. Overall, my postdoctoral work represents an advance in complexity, resolution, and throughput over current in vitro models. Ultimately, my focus on the role of the tumor microenvironment in bone marrow in the ability of DTCs to maintain or escape dormancy provides the foundation toward understanding the highly variable outcomes of different prostate cancer patients.

As I move forward toward establishing my own laboratory in academia, the foundation I have laid in my graduate and postdoctoral work will uniquely position me toward exploring the role of other contributors to cancer progression and dormancy, namely, the contribution of the immune system and the extracellular matrix (Fig. 1c). Example projects for future graduate students include examining the role of different types of T cells in composition of the microenvironment and prostate tumor cell dormancy; modeling the influence of factors secreted by polarized macrophages in tumor cell microenvironment remodeling; and modulating in vitro ECM composition and stiffness to determine effect on tumor cell dormancy. I will seek funding from government (e.g. NIH, NSF) and non-government (e.g. Prostate Cancer Foundation, American Cancer Society) sources. My goal of approaching this complex problem modularly lends itself well to projects to be helmed by multiple graduate students, while an emphasis on cancer will bring a guiding focus to my lab.

Teaching Interests: With a bachelor’s degree in Chemical-Biological Engineering (MIT) and both master’s and PhD in Chemical Engineering (University of Michigan), I am qualified to teach all core chemical engineering classes at the undergraduate and graduate level. I have experience as a Graduate Student Instructor for an undergraduate fluid mechanics course (taught discussion sessions, wrote problem sets and exams, graded; University of Michigan); as an Instructor of Record for the graduate course “BioMEMS and Nanotechnology for Life Sciences” (created and delivered lectures; University of Michigan); and through guest lectures in the course “Introduction to Nanobiology” (lectures on microfluidic approaches to CTC isolation, ethics discussion; UC Berkeley). In addition to this hands-on experience, I furthered my teaching expertise through my work as an Engineering Teaching Consultant and through earning a graduate teacher certificate, both through University of Michigan’s Center for Research on Learning and Teaching. This strong foundation in pedagogy has prepared me to teach existing courses as well as to develop my own. Future courses I would be interested in developing in a Chemical Engineering department include an introduction to biology for students pursuing interdisciplinary research (undergraduate and early graduate level) and applications of engineering research in cancer biology (graduate level), with an emphasis on cellular function and interactions and providing a foundation in laboratory techniques.

Diversity, Equity, and Inclusion (DEI): Fostering an inclusive climate in STEM disciplines begins with acknowledging our own biases, learning about the diversity of experiences and how they are affected by exclusionary practices, and enacting practices to promote equity. I have worked toward these important goals throughout my academic career through implicit bias training, K-12 outreach, and mentoring students in the laboratory setting. By connecting hands-on experimental results and advances in biomedicine that are changing patient care during early interactions with students, I can continue to inspire a passion for research in the next-generation of scientists and engineers and promote inclusion in the laboratory.

Service: I have contributed to the academic community through service at the graduate and postdoctoral level. As a graduate student, I served as Treasurer, Recruitment Co-Chair, and Outreach Co-Chair as a member of the Chemical Engineering Graduate Society, interfacing both with my fellow graduate students and department faculty. As a postdoc, I am a board member of the Berkeley Postdoc Association, where I serve as a member of the Diversity Committee. We host events to educate and promote discussion about diversity and work to improve diversity at the postdoctoral level. I am also a board member of the Postdoc Teaching Opportunities Program, where I work to provide opportunities to practice teaching and obtain meaningful feedback as part of postdoc professional development. Given my prior leadership experience, I look forward to playing a greater role in the professional societies to which I belong, e.g., AIChE, AACR.

In summary, my research has the potential to change the way we study cancer and approach treatment decisions. I am uniquely qualified to lead this research as academic faculty because of my strong engineering expertise, experience in developing and applying technology to biomedical problems, and passion for the challenges put forth by the ever-evolving nature of cancer. Taken together with my extensive teaching experience, my training has provided me with a foundation upon which to build a successful academic program.

References:

(1) Kozminsky, M.; Fouladdel, S.; Chung, J.-S.; Wang, Y.; Smith, D. C.; Alva, A.; Azizi, E.; Morgan, T.; Nagrath, S. Detection of CTC Clusters and a Dedifferentiated RNA-Expression Survival Signature in Prostate Cancer. Advanced Science 2019, 6 (2), 1801254. https://doi.org/10.1002/advs.201801254.

(2) Day, K. C.; Hiles, G. L.; Kozminsky, M.; Dawsey, S. J.; Paul, A.; Broses, L. J.; Shah, R.; Kunja, L. P.; Hall, C.; Palanisamy, N. HER2 and EGFR Overexpression Support Metastatic Progression of Prostate Cancer to Bone. Cancer research 2017, 77, 74–85.

(3) Yoon, H. J.; Shanker, A.; Wang, Y.; Kozminsky, M.; Jin, Q.; Palanisamy, N.; Burness, M. L.; Azizi, E.; Simeone, D. M.; Wicha, M. S. Tunable Thermal‐Sensitive Polymer–Graphene Oxide Composite for Efficient Capture and Release of Viable Circulating Tumor Cells. Advanced materials 2016, 28, 4891–4897.

(4) Scheideler, O. J.; Yang, C.; Kozminsky, M.; Mosher, K. I.; Falcon-Banchs, R.; Ciminelli, E. C.; Bremer, A. W.; Chern, S. A.; Schaffer, D. V.; Sohn, L. L. Recapitulating Complex Biological Signaling Environments Using a Multiplexed, DNA-Patterning Approach. Sci. Adv. 2020, 6, eaay5696.

(5) Kozminsky, M.; Carey, T.; Sohn, L. L. DNA-Directed Patterning for Versatile Validation and Characterization of a Lipid-Based Nanoparticle Model of SARS-CoV-2. 2021. https://doi.org/10.26434/chemrxiv.14208455.v1.

(6) Carey, T. R.; Kozminsky, M.; Hall, J.; Vargas-Zapata, V.; Geiger, K.; Coscoy, L.; Sohn, L. L. Toward Community Surveillance: Detecting Intact SARS-CoV-2 Using Exogeneous Oligonucleotide Labels. medRxiv 2021, 2021.03.23.21254201. https://doi.org/10.1101/2021.03.23.21254201.