My overall career goal is to become an established cancer cell biologist who employs multidisciplinary approaches to determine how phase transition is used to promote cancer cell growth and to develop strategies targeting these processes for cancer therapy. My interest in self-assembly of biological matter originated from my Ph.D. work on molecular dynamics in lipid bilayers and postdoctoral work on phase separation of RNA granules. Supported by the Physical Science Oncology Center (PSOC) at Penn, I started working in cancer in my current postdoctoral position at Penn since 2015 and became interested in cell and molecular physics of cancer. I decided to focus my independent research in this area and initiated a project that I will bring with me to my future laboratory. My project concerns telomerase-negative cancer cells that rely on an alternative lengthening of telomeres (ALT) pathway to maintain telomere length. The presence of ALT- associated promyelocytic leukemia nuclear bodies (APBs) is a unique characteristic of ALT and is used for diagnosis. APBs are essential for telomere maintenance in ALT, but both how they form and how they function in telomere lengthening, which is a crucial part of the ALT cancer phenotype, are unknown. I observed that APBs induced by DNA damage at telomeres exhibit behavior characteristic of liquid phase condensation, leading me to hypothesize that telomere shortening in ALT cells induces nucleation of APB condensates as a mechanism for telomere elongation. The liquid nature of APBs would promote coalescence of APBs to cluster telomeres within APBs, another characteristic of ALT cells. Meanwhile, condensation of APB droplets can concentrate DNA repair factors, providing opportunities for telomeres to use one another as repair templates to elongate within APBs. I developed an optogenetic approach and induced de novo assembly of APBs that exhibit liquid behavior and coalesce to drive telomere clustering. In this K22, I will test my hypothesis for APB function to provide a basis for cancer therapy targeting APBs.
Aim 1 focuses on the dependence of APB function on their material properties by asking how APB formation drives telomere clustering, and Aim 2 focuses on the dependence of APB function on their chemical composition by testing whether APB formation is sufficient for telomere synthesis. I am negotiating my offers for the position of Assistant Professor and plan to start my independent career earlier next year. With my multidisciplinary training background and exciting preliminary data that supports my hypothesis, I am well positioned to achieve my career objectives as an independent cancer researcher. However, to make the transition into cancer research smooth and successful, further training to gain knowledge and technical expertise in cancer biology, particularly on DNA repair and telomere biology, is much needed. Therefore, additional protected time from this K22 is crucial for me to focus on research, immerse in cancer biology, and develop skills bridging expertise from multiple disciplines to establish myself as an expert on liquid phase condensation in cancer.
A significant fraction of cancer cells maintain viability by elongating their telomeres through an alternative lengthening of telomeres (ALT) pathway that is poorly understood. Intracellular structures associated with telomeres, called APBs, have been identified that are a hallmark of these cancers and used for diagnosis, but how these structures form and what they do is unclear. The proposed studies will test a liquid condensation hypothesis for APB assembly and function using innovative optogenetic tools, providing basis for cancer therapy targeting APBs.
