# Regulation of Metastatic Development by Heritable Variants in the Tumor Microenvironment

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $388,875

## Abstract

Project Summary
Metastatic prostate cancer is incurable. Defining the key contributors to metastatic progression within the primary
tumor will have broad implications for clinically translatable targets for both the early identification of who is at
risk for metastatic cancer and for the treatment of cancer. In patient based data, we have identified germline
variants in the length of the aspartate (D) repeat domain of Asporin (ASPN) that are either associated with (D14)
or are protective of (D13) metastatic development. We reported that opposed to being expressed in cancer cells,
ASPN expression is highly enriched in cancer associated fibroblasts (CAFs), and its expression is significantly
associated with local cancer aggressiveness as measured by Gleason grade. Consistent with patient-based
data, in vivo models of tumor-stromal interactions, support that expression in the tumor microenvironment of
ASPN D14 drives while ASPN D13 restricts metastatic development. Our data suggest that ASPN has potential
clinical utility to better stratify disease aggressiveness for treatment decision making and may also be a potential
therapeutic target due to its extracellular expression in the tumor microenvironment. Despite its high potential for
clinical significance, the role of ASPN in local tumor aggressiveness or metastatic development has not been
fully determined. Furthermore, the cellular and molecular mechanisms by which ASPN regulates metastatic
progression are also incompletely defined. However, our preliminary data suggest that ASPN may regulate
pluripotency and self-renewal of CAF progenitors, which may be a key mechanism for how ASPN regulates local
progression and metastatic potential. Based on these new findings, we aim to identify the mechanisms by which
ASPN regulates tumor progression. Our central hypothesis is that ASPN maintains CAF progenitors, and
thereby ASPN potentiates CAF-induced invasion and progression to metastasis. We further hypothesize
that the length of the D-repeat domain in ASPN affects its mechanistic and cellular functions and
ultimately its impact on metastatic development. Our goals are 1) to determine the contribution of ASPN to
primary tumor growth and metastatic development in autochthonous animal models, and to delineate the 2)
cellular and 3) molecular based mechanisms by which ASPN D14 promotes and ASPN D13 restricts tumor
progression and metastatic-invasion of prostate cancer. We propose to comprehensively examine the role of
ASPN in local cancer aggressiveness and metastatic development using novel in vivo animal models, cutting
edge in vitro assays, and patient-based data. Successful completion of these aims will provide critical information
on how ASPN regulates metastatic development, and will therefore provide opportunities for translating these
findings for prognosis and therapy.

## Key facts

- **NIH application ID:** 9828536
- **Project number:** 5R01CA211695-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Paula Jill Hurley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,875
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828536

## Citation

> US National Institutes of Health, RePORTER application 9828536, Regulation of Metastatic Development by Heritable Variants in the Tumor Microenvironment (5R01CA211695-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828536. Licensed CC0.

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