Cellular Hierarchy
Abstract
Tumors contain millions of cancer cells that may come in different size and shape and that interact with a wide range normal cells from the host/patients. The interplay between cancer cells with different cell types of the microenvironment are fundamental for growth and metastatic dissemination. Melanoma, the most aggressive type of skin cancer, exhibits a high degree of heterogeneity and becomes lethal once cells metastasize to distant organs. Thereby, there is an unmet need to understand how different cell populations contribute to tumor growth, metastasis and eventually therapy resistance. By generating new sophisticated mouse models to trace melanoma cells and combining them with new cutting-edge technologies at single cell resolution we unraveled the identity and the spatial distribution of each cell within a given melanoma tumor. We uncovered an extensive melanoma heterogeneity and identified a small fraction of cells that harbors stemness characteristics. Cancer Stem Cells (CSCs) have been proposed to be the main source of tumor growth in different types of cancer, however in melanoma their existence and their functional role remain elusive. This implies that not all cells are fated to fuel growth and supports that not every cell is equal with each other. Combining advanced imaging and mathematical modeling we demonstrated that growth is hierarchically organized and the melanoma stem-like population is likely sitting at the top of a developmental hierarchy. We observed that, these so called pre-EMT NC-like cells, are spatially localized in close proximity to blood vessels, forming a perivascular niche that favors cells to acquire stemness properties and subsequently fuel tumor growth. We demonstrated that Endothelial Cells (ECs), one of the main components of the perivascular niche, are one of the major players that favor stemness acquisition in a dynamic manner.
On the contrary, another population of cells, within these heterogeneous tumors, was exhibiting features of invasive/mesenchymal properties, implying that these cells are prone to metastasize to distant organs. We devised a strategy to trace these cells in mice and we generated a new model, called Met-Track. By tracing these cells, we observed that a high fraction of them is spatially localized deeper in the dermis of primary tumors. Once metastasize and colonize distant organs these cells switch identity and start to proliferate again. This is a prime example of cellular plasticity and suggests that cells have not fixed identity, but they rather switch from one state to another finding ways to “escape” from primary tumors and adapt to their new environments.
Overall, our data provide a spatio-temporal map of melanoma heterogeneity suggesting that that distinct pools of cells that are spatially distributed in different cellular niches are fated for growth and for metastatic dissemination.
Data Availability
Single cell RNA sequencing data in mouse melanoma tumors