# Autophagy and mTORC1 signaling in lymphatic malformation and lymphangiosarcoma

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2021 · $409,514

## Abstract

Summary/Abstract
Lymphangiosarcoma (LAS) is angiosarcoma with lymphatic differentiation that originates from the malignant
transformation of endothelial cells (ECs). The etiology of LAS is largely unknown, although lymphatic
malformation (e.g. chronic lymphedema in breast cancer patients) has been recognized as a risk factor for the
disease. The long-term goal of the proposed studies is to understand the molecular and cellular mechanisms
of lymphatic malformation and progression to LAS in order to develop new strategies for effective therapies of
this deadly disease. In the previous funding period, we created a mouse model with inducible EC-specific
deletion of Tsc1 which recapitulates salient features of human LAS, and showed that hyper-activation of
mTORC1 and increased VEGF autocrine signaling in ECs were required for initiation and maintenance of LAS.
In further preliminary studies, we discovered that maintenance of hyper-activation of mTORC1 in TSC-deficient
cells required autophagy under glucose-starvation, but not amino acid-starvation or normal conditions.
Moreover, autophagy maintains elevated levels of ATP specifically through lipid catabolism and generation of
fatty acids as the main source of ATP under these energy stress conditions. In addition, consistent with clinical
findings that malignant transformation of vascular malformation to angiosarcoma was accompanied with
secondary mutations, preliminary studies employing whole exome sequencing (WES) of LAS samples from our
Tsc1iΔEC mice model identified secondary mutations in several genes including Cdk6, which is involved in cell
cycle regulation and implicated in other cancers. Based on these strong preliminary studies and using our
unique novel mouse models, we propose to 1) determine the mechanisms of autophagy in the regulation of
lipolysis to produce fatty acids as an alternative fuel for ATP production to maintain mTORC1 hyper-activation
in Tsc1-null vascular tumor cells; 2) examine the role of autophagy-mediated lipid catabolism in maintaining
mTORC1 hyper-activation in lymphatic malformation and LAS in vivo and evaluate potential therapeutic
efficacy of targeting autophagy-mediated lipolysis in mouse and PDX models of lymphatic malformation and
LAS; and 3) explore the roles and mechanisms of secondary mutations in Cdk6 and other genes in the
development of lymphatic malformation and progression to LAS. Together, the proposed studies to examine
reverse regulation of mTORC1 by autophagy through novel mechanisms of lipid metabolism as well as
secondary mutations that synergizing with mTORC1 signaling will provide significant mechanistic insights into
the disease, which may contribute to novel therapies for this devastating disease.

## Key facts

- **NIH application ID:** 10242776
- **Project number:** 5R01HL073394-17
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** JUN-LIN GUAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,514
- **Award type:** 5
- **Project period:** 2003-04-08 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242776

## Citation

> US National Institutes of Health, RePORTER application 10242776, Autophagy and mTORC1 signaling in lymphatic malformation and lymphangiosarcoma (5R01HL073394-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242776. Licensed CC0.

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