Principal Investigator: Alexander Nikitin

DESCRIPTION (provided by applicant): 

Ovarian/extra-uterine high-grade serous carcinoma (HGSC) is the most common and aggressive type of ovarian cancer. It often has no symptoms at early stages and over 80% of patients are diagnosed at advanced, usually incurable, cancer stages, when the tumors have already metastasized. Extensive integrated genomic analysis allowed identification of several clinically distinct subtypes of HGSC. A significant fraction of HGSC arises from the tubal epithelium (TE) located in the distal region of Fallopian tube (aka uterine tube or oviduct). Recent single cell transcriptome analysis of distal TE inferred that HGSC heterogeneity could be connected to diverse cell states present in TE cell lineages. Unfortunately, precise cell lineage-based hierarchy of identified TE cell types has not been yet established. Furthermore, cancer-prone cellular states of TE are insufficiently defined and factors influencing such states remain unclear. Thus, it remains unknown if uneven clinical course of HGSC anddevelopment of cellular therapeutic responses may reflect different modes of initiation and progression of this malignancy. Our preliminary studies show that, in addition to known secretory (OVGP1+) and ciliated (FOXJ1+, CD24+) epithelial cells, there are several epithelial cell populations characterized by preferential expression ofstem/progenitor cell markers, such as SLC1A3, CD49f (ITGA6), and KLF6. A Monocle cell-lineage trajectory prediction analysis of our single-cell transcriptomic data identified a population of SLC1A3+ stem/progenitor cells that give rise to both secretory and ciliated cells by progressing through transient intermediates, including aKRT5+ cell population. This prediction has been confirmed by lineage tracing of SLC1A3+ cells and ex vivo studies. Cells in a transient state (CD24med CD49f+) form spheres in consecutive rounds of sphere dissociation regeneration and express KRT5. Under normal homeostatic conditions, KRT5+ cells are largely dormant and minimally contribute to secretory and ciliated cell lineages. However, KRT5+ cells become actively involved in re-epithelialization after mechanical damage. Our preliminary results suggest that stromal charges begin to coevolve with mutant epithelial cells before the earliest morphologically detectable alterations. Based on previous studies and our preliminary results we hypothesize that cancer-prone TE cell states are determined by levels of epithelial damage and stromal milieu changes. To test this hypothesis we propose (1) to establish the role of specific cell states during homeostatic and posttraumatic regeneration, (2) to determine the impact of epithelial damage on cancer susceptibility of epithelial states and (3) to identify and characterize epithelial and stromal cell lineage dynamics during early stages of TE malignant transformation.