# A novel, glutathione-dependent metabolic pathway drives metastatic outgrowth in pancreatic cancer

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $485,558

## Abstract

Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer-related death in the US, for which
treatment remains basically unchanged in the past three decades. Although patients often die from metastatic
lesions, there are no specific diagnostic markers or therapeutic strategies aimed at treating metastases,
particularly due to an almost complete lack of knowledge on the molecular drivers of metastatic progression.
Using differential gene expression analysis of matched primary tumors and metastasis from genetically
engineered mouse models of PDA, a novel functional soft-agar screen, and subsequent validation studies in
human specimens we identified a novel glutathione-related metabolic pathway specifically activated in
metastatic cells. Critically, inducible ablation of two key factors in the pathway, Gstt1 (glutathione S-transferase
theta 1) and the aminoacid transporter Slc38a4, that are specifically expressed in metastatic lesions,
completely halted the growth of metastases without affecting the primary tumors; these genes are only
expressed in normal liver cells, suggesting that metastatic cells co-opt this pathway and repurpose it for
metabolic fitness; furthermore, preliminary data indicate that such adaptation drives a novel conjugating activity
(glutathyonylation) of matrix proteins including fibronectin 1 (Fn1) to allow metastatic cells to better expand
within the extracellular matrix (ECM), all together indicating that these lesions evolve by acquiring non-genetic
adaptations. In this proposal, we will take advantage of biochemistry, cell biology, genetically-engineered
mouse models and samples from human patients in order to molecularly characterize these factors, with the
potential to change treatment for this devastating disease.

## Key facts

- **NIH application ID:** 10800437
- **Project number:** 1R01CA279173-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Raul Mostoslavsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $485,558
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800437

## Citation

> US National Institutes of Health, RePORTER application 10800437, A novel, glutathione-dependent metabolic pathway drives metastatic outgrowth in pancreatic cancer (1R01CA279173-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10800437. Licensed CC0.

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