# Analysis of epithelial heterogeneity in prostate development and cancer

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $419,416

## Abstract

Project Summary
 The cell type that undergoes cancer initiation, or “cell of origin,” plays a key role in determining tumor
properties such as molecular and histopathological subtype as well as treatment response and disease
outcome. In the case of prostate cancer, the cell of origin may be highly relevant for whether it is indolent or
aggressive, and consequently the analysis of cell types of origin may lead to identification of biomarkers that
can guide therapy. Over the past ten years, our laboratory has made considerable progress in understanding
prostate cell types of origin through studies of the progenitor populations, lineage relationships, and
transcriptional regulators of the prostate epithelium during normal development as well as cancer initiation and
progression. In preliminary studies for this proposal, we have performed single-cell RNA sequencing to
examine the heterogeneity of prostate epithelial cells in the benign mouse and human prostate. Notably, these
analyses have revealed several different luminal populations that have not been previously identified, and may
represent distinct cell types of origin. Furthermore, we have used computational systems approaches to
identify candidate master regulator (driver) genes for these novel luminal populations. Finally, we have
established three-dimensional organoid culture conditions to investigate whether specific mouse and human
epithelial cell populations are cell types of origin for prostate cancer.
 Based on our preliminary data, we hypothesize that analysis of the origin and drivers of specific
epithelial populations in the prostate will elucidate cell types of origin for prostate cancer as well as their roles
in specifying tumor phenotypes. To investigate this hypothesis, we will pursue an innovative combination of in
vivo, ex vivo, molecular, and computational systems approaches using genetically-engineered mouse models
and human prostate tissue. We propose three specific aims: (1) Investigation of epithelial heterogeneity in the
developing and adult prostate using single-cell transcriptomics to examine the origin and lineage relationships
of distinct epithelial populations and identify drivers that specify these populations; (2) Analysis of cell of origin
in mouse and human prostate using organoid culture approaches to determine whether distinct luminal and
basal epithelial populations can give rise to tumors after oncogenic transformation and identify candidate
master regulators of this process; and (3) Investigation of epithelial heterogeneity in mouse and human
prostate cancer using cross-species single-cell analyses to identify conserved drivers of tumor heterogeneity.
Taken together, our studies will provide fundamental molecular and functional insights into prostate epithelial
heterogeneity during development and tumorigenesis, and will have important implications for understanding
the origins of human prostate cancer and its treatment.

## Key facts

- **NIH application ID:** 9873004
- **Project number:** 5R01CA238005-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** MICHAEL M. SHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,416
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873004

## Citation

> US National Institutes of Health, RePORTER application 9873004, Analysis of epithelial heterogeneity in prostate development and cancer (5R01CA238005-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873004. Licensed CC0.

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