# Mechanisms regulating the formation of a pro-metastatic niche and tumor cell dormancy in the liver

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2022 · $39,505

## Abstract

ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related deaths in the United
States. For patients with PDAC, metastasis is the major cause of mortality and the liver is the most common site
of metastasis. Thus, therapies capable of disrupting the metastatic process represent a clear unmet need.
Recent work in the lab showed that Serum Amyloid A1/2 proteins (SAA) released during cancer development
precondition the liver for metastasis. In this process, a “pro-metastatic niche” forms in the liver that supports the
seeding and colonization of disseminated tumor cells (DTCs). Notably, SAA is a known determinant of liver
biology acting via toll-like receptors (TLRs) expressed by innate immune cells. SAA has also been shown to
orchestrate an acute phase inflammatory response and to promote tissue repair. However, the mechanisms by
which SAA directs formation of a pro-metastatic niche in the liver, and the impact of this niche on the fate of
DTCs seeding the liver, remain ill-defined. Thus, an understanding of this biology has strong potential to inform
the development of novel strategies aimed at derailing the metastatic cascade. Preliminary data show expression
of SAA receptors on macrophages isolated from normal livers, in vitro induction of TLR2 and TLR4 reporter
signals by SAA, and increased expression of TLR2 and TLR4 on macrophages within the niche. These data
suggest that TLR signaling is a key determinant of the pro-metastatic niche. Preliminary data also show that, in
the absence of a pro-metastatic niche, DTCs encountering the liver enter a dormant state. This finding suggests
the need for a secondary cue to “awaken” dormant cancer cells and to trigger metastatic outgrowth. Consistent
with this, recent studies have shown a role for migratory myeloid cells in reversing tumor cell dormancy in the
lung. Similarly, my preliminary data show an accumulation of inflammatory monocytes within the niche that forms
in the liver. Thus, the central hypothesis of this proposal is that SAA released by hepatocytes activates
resident liver macrophages via TLR signaling to direct the formation of a pro-metastatic niche and
ultimately direct the fate (i.e. dormancy versus outgrowth) of DTCs in the liver. In Aim one, I will determine
the mechanisms by which SAA directs formation of the pro-metastatic niche. In Aim two, I will elucidate the
impact of the pro-metastatic niche on DTC fate in the liver. Altogether, studies in this proposal will advance our
understanding of the metastatic process with the potential to identify novel therapeutic approaches for
intervening on cancer metastasis. In addition, this project will be sponsored by an established mentor with
expertise in immunology and cancer biology. This sponsorship involves a commitment to mentorship and will
occur at one of the foremost institutions in cancer immunology and cancer biology. This project also
encompasses a graduate training plan which complements trainin...

## Key facts

- **NIH application ID:** 10395452
- **Project number:** 5F31CA261124-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jesse Lee
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,505
- **Award type:** 5
- **Project period:** 2021-04-01 → 2023-12-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10395452

## Citation

> US National Institutes of Health, RePORTER application 10395452, Mechanisms regulating the formation of a pro-metastatic niche and tumor cell dormancy in the liver (5F31CA261124-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10395452. Licensed CC0.

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