Abstract
Disclosure: T. Henson: None. M. Wines-Samuelson: None. R. Myers: None. S.R. Hammes: None.
Lymphangioleiomyomatosis (LAM) is a rare multisystemic disease associated with the development of lung cysts caused by small smooth muscle cell tumors throughout the lungs. These cysts lead to a loss of lung function that ultimately can require lung transplantation. Mutations in the genes encoding the tuberous sclerosis complex (TSC21 or TSC2) are the cause of LAM tumors. These mutations lead to increased signaling by mammalian target of rapamycin complex 1 (mTORC1), ultimately causing proliferation of the smooth muscle cells. LAM is a sexually dimorphic disease that almost exclusively affects genetic females. Clinical observations implicate the role of estrogen in disease progression, as it is exacerbated during pregnancy and stabilizes with menopause. LAM has been shown to be metastatic, with reoccurrence after lung transplantation. With these features, our lab proposed that LAM cells may originate from the estrogen sensitive uterine myometrium. This hypothesis was addressed by creating a mouse model whereby TSC2 expression was specifically knocked out in the mouse uterus. TSC2-null mice developed myometrial overgrowth with most features of LAM, and 50% of mice developed lung metastases, confirming a potential myometrial origin of LAM. These findings in mice were supported by later single cell RNA sequencing of human lung LAM cells showing a strong uterine signature. In our uterine-specific TSC2-null mouse model, myometrial growth was almost completely estrogen dependent. However, in vitro work with primary mouse TSC2-null myometrial cells revealed lesser responses to estradiol (E2), indicating that direct E2 stimulation may not be solely responsible for tumor progression. In fact, we found that estradiol, in combination with tumor factors, promotes neutrophil production in the bone marrow, which in turn drives tumor growth. Here we performed transcriptomics on mouse bone marrow from uterine-specific TSC2-null nice and their normal littermates. Interestingly bulk messenger RNA sequencing of bone marrow-derived neutrophils revealed an increase in gene expression associated with nearly every enzyme in the cholesterol biosynthesis pathway in neutrophils isolated from tumor burdened TSC2-null mice, suggesting that cholesterol may be an important regulator of neutrophil function in response to tumor-derived factors. Further studies are investigating the combinatorial role of tumor derived factors with estrogen on the transcriptome of bone marrow, again focusing on transcriptomic changes that regulate neutrophil production and actions.
Presentation: Sunday, July 13, 2025