# Mechanisms of progression of vascular malformation to lymphangiosarcoma

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $487,993

## Abstract

Summary/Abstract
 Endothelial cells (ECs) are key components of both blood and lymphatic vessels, and aberrant EC
proliferation due to abnormalities in various signaling pathways contributes to a wide range of vascular anomalies
including vascular malformation and tumors. Lymphatic malformation (LM) and lymphangiosarcoma (LAS) are
vascular anomalies originating from lymphatic ECs. While LM mostly remains as a benign disease, a fraction of
LM patients progress to the highly aggressive and deadly LAS. Although LM (e.g. chronic lymphedema in breast
cancer patients) has been recognized as a risk factor for LAS, very little is known about underlying mechanisms
regulating the progression of LM to LAS. The long-term goal of the proposed studies is to understand the
molecular and cellular mechanisms of LM progression to LAS in order to develop new strategies for effective
prevention and treatment of this deadly disease. In prior funding periods, we developed a mouse model with
inducible EC-specific deletion of Tsc1 tumor suppressor gene (Tsc1iΔEC mice), which recapitulates salient
features of human LAS. Using a new tumor cell line derived from Tsc1iΔEC mice, we further showed that
autophagy blockade by knockout or knockdown of different autophagy genes inhibited vascular tumor cell
proliferation in vitro and tumorigenicity in vivo. Transcriptional profiling and additional mechanistic analysis
suggested a role for the autophagy-dependent expression of osteopontin and its potential autocrine stimulation
of Jak/Stat3 signaling in promoting tumor cell proliferation and tumorigenicity. More importantly, by generating
EC-specific double conditional knockout of an essential autophagy gene Fip200 in Tsc1iΔEC model, we found that
autophagy inhibition, while not affecting the initial LM development, blocked LM progression to LAS. We also
prepared a new Tsc1/Fip200-4A double conditional knockin mouse for further analysis of the mechanisms of
regulation of LM progression to LAS by FIP200-mediated autophagy in vivo. In addition, we performed a genome-
wide CRISPR-Cas9 screen and identified several genes with tumor suppressive functions for vascular tumor
growth in vivo, including Rasa1 encoding a negative regulator of Ras signaling, suggesting potential synergy
between Ras/MAPK and mTORC1 signaling in LM development and progression to LAS. Based on these strong
supporting data and using our unique mouse and cell models, we propose to 1) determine the mechanisms of
autophagy regulation of vascular tumor cell proliferation and tumorigenicity; 2) examine targeting of autophagy
and its downstream pathways to block LM progression to LAS; and 3) explore the potential synergy between
Ras and mTORC1 signaling in the development and progression of vascular tumors. Together, these studies
will significantly advance our understanding of the molecular and cellular mechanisms of LM progression to LAS,
that may contribute to the future design of effective prevention and novel ther...

## Key facts

- **NIH application ID:** 10445196
- **Project number:** 2R01HL073394-18
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** JUN-LIN GUAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $487,993
- **Award type:** 2
- **Project period:** 2003-04-08 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445196

## Citation

> US National Institutes of Health, RePORTER application 10445196, Mechanisms of progression of vascular malformation to lymphangiosarcoma (2R01HL073394-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10445196. Licensed CC0.

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