# Cancer-prone cell states of the fallopian tubal epithelium

> **NIH NIH R01** · CORNELL UNIVERSITY · 2022 · $420,922

## Abstract

Project Summary
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 and
development 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 of
stem/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 a
KRT5+ 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 co-
evolve 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.

## Key facts

- **NIH application ID:** 10397606
- **Project number:** 5R01CA260115-02
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Alexander Y. Nikitin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $420,922
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397606

## Citation

> US National Institutes of Health, RePORTER application 10397606, Cancer-prone cell states of the fallopian tubal epithelium (5R01CA260115-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10397606. Licensed CC0.

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