Related Experiment Video
Updated: Oct 1, 2025
A Preclinical Murine Model of Hepatic Metastases
Published on: September 27, 2014
Ligand-mediated PAI-1 inhibition in a mouse model of peritoneal carcinomatosis
Josephine Hendrikson1,2,3, Ying Liu1,2,3, Wai Har Ng1,2,3
1Department of Sarcoma, Peritoneal and Rare Tumours (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Cresent, Singapore 169610, Singapore.
Abstract:
Peritoneal carcinomatosis (PC) present a ubiquitous clinical conundrum in all intra-abdominal malignancies. Via functional and transcriptomic experiments of ascites-treated PC cells, we identify STAT3 as a key signaling pathway. Integrative analysis of publicly available databases and correlation with clinical cohorts (n = 7,359) reveal putative clinically significant activating ligands of STAT3 signaling. We further validate a 3-biomarker prognostic panel in ascites independent of clinical covariates in a prospective study (n = 149). Via single-cell sequencing experiments, we uncover that PAI-1, a key component of the prognostic biomarker panel, is largely secreted by fibroblasts and mesothelial cells. Molecular stratification of ascites using PAI-1 levels and STAT3 activation in ascites-treated cells highlight a therapeutic opportunity based on a phenomenon of paracrine addiction. These results are recapitulated in patient-derived ascites-dependent xenografts. Here, we demonstrate therapeutic proof of concept of direct ligand inhibition of a prognostic target within an enclosed biological space.
Insights
We identified STAT3 signaling as crucial in peritoneal carcinomatosis (PC). A new 3-biomarker panel predicts prognosis, revealing a therapeutic target for intra-abdominal malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling Pathways
Background:
- Peritoneal carcinomatosis (PC) poses a significant challenge across various intra-abdominal malignancies.
- Understanding the molecular mechanisms driving PC is critical for developing effective treatments.
Purpose of the Study:
- To identify key signaling pathways involved in peritoneal carcinomatosis.
- To develop a prognostic biomarker panel for PC.
- To explore therapeutic strategies targeting identified pathways.
Main Methods:
- Functional and transcriptomic analysis of ascites-treated PC cells.
- Integrative analysis of public databases and clinical cohorts (n=7,359).
- Prospective validation of a 3-biomarker panel (n=149) and single-cell sequencing.
Main Results:
- STAT3 signaling was identified as a key pathway in PC.
- A 3-biomarker panel, including PAI-1, was validated for prognostic significance.
- PAI-1 is primarily secreted by fibroblasts and mesothelial cells.
- Therapeutic targeting of STAT3 signaling demonstrated proof of concept in preclinical models.
Conclusions:
- STAT3 activation and PAI-1 levels in ascites can stratify patients and indicate therapeutic opportunities.
- Targeting ligand-dependent STAT3 signaling presents a viable therapeutic strategy for PC.
- This study provides a foundation for novel treatment approaches for peritoneal carcinomatosis.
