# Uterine signaling networks in the pathogenesis of pulmonary lymphangioleiomyomatosis (LAM)

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $770,161

## Abstract

PROJECT SUMMARY
Lymphangioleiomyomatosis (LAM), a lung neoplasm affecting reproductive age women, is caused by loss-of-
function mutations in tuberous sclerosis 1 (TSC1) or TSC2 genes. Hyperactivation of the mechanistic target of
rapamycin 1 leads to cystic lung remodeling and progressive respiratory failure. Sirolimus therapy stabilizes lung
function and improves symptoms in LAM patients, but the long-term benefit and toxicity are unknown, and some
patients do not respond to therapy. LAM cells are metastatic but the primary tissue of origin is unknown.
Unknown mechanisms underlying lung-specific metastasis, primary pathogenesis and female prevalence of LAM
are obstacles to the development of new curative therapies. Our preliminary data from LAM lung single cell
RNA sequencing (scRNAseq) analysis identified a unique population of cells (LAMCORE) expressing uterine-
specific homeobox (HOX) transcription factors (TFs) that are not detected in normal lung; TF profiling of LAM
patient-derived cells identified activation of Pre-B-cell leukemia homeobox 1 (PBX1), a cofactor of HOXs;
comparative analysis of LAM lung scRNAseq and breast cancer cell PBX1-ChIPseq revealed overly represented
LAMCORE signature genes with positive PBX1 binding peaks. Collectively, this strongly suggests a uterine origin
of LAM cells and a central role of HOX/PBX1 signaling in LAM pathogenesis. The objective of this proposal is
to identify mechanisms by which HOXs-associated gene networks regulate LAM pathogenesis and progression.
Our central hypothesis is that HOX/PBX1 orchestrates a cell-specific gene network downstream of female
hormones that regulates the survival and lung metastasis of LAMCORE cells. Three specific aims are proposed to
delineate the molecular mechanisms through which HOX/PBX1 gene network contributes to LAM lesion
metastasis, formation and progression. Aim 1: Determine pulmonary LAM-specific genomic and epigenomic
responses and mechanisms underlying HOX/PBX1-mediated LAM pathogenesis. Aim 2: Determine the
functional impacts of HOX/PBX1 network genes on metastatic potentials of LAM-derived cells in vitro and in vivo.
Aim 3: Determine the effect of the HOX/PBX1 antagonist, HXR9, singly or in combination with Sirolimus, on
estrogen-promoted lung metastasis potentials and lung remodeling in vivo. The completion of this proposal
will provide for the first time: 1) a high-resolution integrative genomic/epigenomic blueprint of the LAMCORE
cells, 2) a LAMCORE cell-specific HOX/PBX1 gene network with predicted key regulatory factors and targets within
the network for follow-up perturbation and clinical diagnostic tests, 3) novel mechanistic insights into HOX/PBX1
regulatory circuits and their functional impact on LAM pathogenesis, and 4) preclinical proof-of-principle evidence
for targeting HOX/PBX1-regulated female hormone-mediated LAM progression as a novel remission-inducing
therapeutic strategy for LAM patients. Our work has major biomedical relevance for unde...

## Key facts

- **NIH application ID:** 10221045
- **Project number:** 5R01HL153045-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** YAN XU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $770,161
- **Award type:** 5
- **Project period:** 2020-07-21 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221045

## Citation

> US National Institutes of Health, RePORTER application 10221045, Uterine signaling networks in the pathogenesis of pulmonary lymphangioleiomyomatosis (LAM) (5R01HL153045-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10221045. Licensed CC0.

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