Zooming in on Cellular Plasticity: Unveiling Cancer Cells Secrets and gaining Therapeutic Insights using Intravital Microscopy

Abstract

Cancer is a broad term encompassing various disease. One common characteristic among all types of cancer is the exploitation of physiological processes to their advantage. This exploitation typically involves acquisition of genetic mutations, often in conjunction with alterations in the immediate environment. The ability of cancer to manipulate the body's own mechanisms, possess significant challenges to battle the disease. Therefore, it is crucial to possess in-depth knowledge about different cancer cells, their behavior, and their interaction with adjacent "healthy" cells. This understanding plays a pivotal role in optimizing cancer treatments in the long run. This dissertation utilizes intravital microscopy to gain fundamental insights into the mechanisms exploited. Hereby we focused not only on mechanisms cancer hijack from healthy tissue but also how this can influence cancer treatment. The first chapter provides a comprehensive summary of recent advancements in the field of tumor cell dynamics and plasticity, were we particularly have focused on migration behavior and spreading of cancer to other organs (Chapter 1). Migration is a process frequently exploited by cancer cells. In healthy tissue, migration is important for wound healing in the skin. Therefore, we examined migration behavior of keratinocytes in a "healthy", cancer-free skin. Our intravital microscopy observations revealed dynamic movement of keratinocytes, much more than previously thought, which likely facilitates wound healing, even in the presence of obstacles like hair roots (Chapter 2). Next, we explored epithelial-to-mesenchymal transition (EMT), an embryonic process also frequently employed by tumor cells. We assess and discuss our current understanding of EMT, reviewing historical studies in light of recent insights, such as hybrid E/M states (Chapter 3). Additionally, we developed various tumor models enabling visualization of different hybrid E/M states in the same cell over time. Through this, we demonstrated that EMT is a spectrum of distinct cellular states (Chapter 4) challenging the previous held belief of it being binary process. We also discovered that cells in an early hybrid E/M state exhibit the highest potential for metastasis and resistance to chemotherapy (Chapter 5). In the final chapters, we investigated influences of environmental factors on the behavior and dynamics of tumor cells, examining both microenvironmental and systemic influences. We demonstrated that CD8+ T-cell activity, particularly release of INFγ over long distances within the tumor, can be influence tumor cell behavior (Chapter 6). Furthermore, we explored the impact of the menstrual cycle on the behavior of breast tumor cells and revealed that tumor cells mimic behavior of healthy breast tissue. Additionally, we discovered that treatment is more effective when chemotherapy is synchronized with the hormonal cycle (Chapter 7). The diversity of the different chapters underscores the significance considering multiple factors to gain better understand of cancer and consequently enhance treatment outcomes. While we have still not fully grasped the its entire complexity, this dissertation demonstrates that tumor cells themselves, their cellular state, their immediate environment, and the entire organism can all play a role in the success of therapies. To improve treatments, it is important to expand this knowledge in the future.