Engineering Biomaterials to Modulate the Tumor Immune Microenvironment - Cancer remains a significant global health challenge, with an anticipated 611,240 deaths in 2024. Substantial strides in cancer research have enhanced our understanding of the mechanisms underlying its development, progression, and spread. While current treatments such as surgery, radiation, chemotherapy, targeted therapy, and immunotherapy have shown efficacy in certain cases, drug resistance poses a pervasive challenge. Resistance often leads to cancer cells regenerating into new tumors with altered molecular profiles that diminish drug effectiveness. Alternatively, cancer cells can adapt during treatment, acquiring genetic mutations that allow them to evade therapeutic effects. One approach to address this issue is combining different therapies to restore sensitivity in resistant cells. However, the molecular heterogeneity of cancer remains a significant barrier, contributing to treatment resistance and subsequent relapse. Therefore, it is crucial to comprehensively understand how various treatments induce specific molecular changes within both the tumor and its microenvironment, and how these changes influence the diverse outcomes observed in cancer therapy. In this proposal, I will evaluate the response of different cancer therapy modalities in various cancer types. I will employ high-dimensional single-cell approaches to identify differential gene expression driven by the different anticancer treatments and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatments, respectively. Further, I will develop analytical tools to identify ligand-receptor interactions between the tumor and its surrounding microenvironment that could be used as therapeutic targets, and to gain a unique insight into how tumors, their microenvironment, and the host respond to different treatments. Lastly, I will engineer ex vivo and in vitro culture systems that recapitulate the complexity of the tumor microenvironment, particularly to study the previously identified interactions, and establish them as 3D co-culture platforms for therapeutic target validation and high-throughput drug screening for my research program. Completion of this project will successfully prepare me to launch an NIH-funded research laboratory engineering cancer-oriented nano-systems to target interactions in the tumor microenvironment that contribute to cancer progression and resistance.
