# Role of Gstt1 in metastatic maintenance and self-renewal in PDA

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $156,330

## Abstract

PROJECT SUMMARY
Only 0.01% of cancer cells enter circulation, survive & produce metastasis, however, metastatic disease
accounts for 90% of cancer-related deaths. In pancreatic ductal adenocarcinoma (PDA), the majority of patients
present with extra-pancreatic invasion and metastatic disease for which the there is a dismal five-year survival
rate and no specific therapeutic strategies directed at the treatment of metastatic disease. Notably, much of the
research into the mechanisms of metastasis has been focused on identifying early drivers within primary tumors,
however, the identification of central drivers of metastatic outgrowth within established lesions largely remain
unexplored. Recently, we have demonstrated that SIRT6 inactivation dramatically accelerates PDA
development, resulting in highly aggressive metastatic disease in the Kras-p53 GEM model. Employing this
highly aggressive PDA metastasis model, in addition to an established breast cancer metastasis model, this
study aims to identify potential vulnerabilities of metastatic lesions that could be exploited to treat patients with
advanced metastatic disease. Performing unbiased RNA-Seq on matched primary and metastatic tissues
followed by a newly developed 96-well soft agar screen, we identified factors that are uniquely required for
anchorage-independent growth of established metastatic cells. Utilizing this functional screen and validation, we
have identified Gstt1 (glutathione S-transferase theta 1) as a top candidate driver of metastatic outgrowth in
multiple mouse models of metastasis. Preliminary data demonstrates that Gstt1 is differentially expressed in
metastatic cell lines compared to matched primary-derived cell lines and inhibition of Gstt1 significantly reduced
metastatic potential of metastases-derived cells, without affecting primary tumor growth, suggesting an important
role for Gstt1 in the outgrowth of established metastatic lesions. Additionally, within metastatic lesions, Gstt1
shows a heterogenous expression pattern, where Gstt1high cells represent an aggressive, non-proliferative sub-
population. Additionally, we have demonstrated that Gstt1 is required for the formation of tumor spheres in breast
and PDA metastatic-derived cell lines in vitro, suggesting a role for Gstt1 as a driver of self-renewal in metastatic
cells. In this proposal we seek to identify characteristics unique to Gstt1high PDA-derived metastatic lesions. The
proposed studies will provide important preclinical demonstration of whether Gstt1 and its downstream targets
are required for sustained growth of metastatic tumors, thus identifying a possible therapeutic window for this
subset of metastatic PDA.

## Key facts

- **NIH application ID:** 10041399
- **Project number:** 1K99CA252600-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Christina Ferrer
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,330
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-07-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10041399

## Citation

> US National Institutes of Health, RePORTER application 10041399, Role of Gstt1 in metastatic maintenance and self-renewal in PDA (1K99CA252600-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10041399. Licensed CC0.

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