Human liposarcoma (LPS) is a deadly and the most common soft tissue cancer whose cellular origin and molecular regulation are unclear. Using a novel transgenic mouse model, we made a seminal discovery in our unpublished preliminary results that aberrant activation Notch signaling in mature adipocytes drives their dedifferentiation and formation of LPS. Notch signaling is an evolutionarily conserved signal transduction cascade that plays an important role in development, cell-cell communication and stem cell differentiation. Aberrant Notch activity has been implicated in several types of cancers including leukemia, breast cancer and osteosarcoma but its role in LPS has not been reported. While our series of preliminary studies have established the adipocyte origin and pathogenic process of LPS in the mouse model, several imperative questions stood out to be addressed in the proposed work. First, we will distinguish the relative role of Notch activity and metabolic dysfunction ? an accompanying feature of the LPS transgenic mouse model ? in the development and pathogenesis of LPS. Second, we will investigate the role of Notch signaling in human liposarcomas. Third, we will dissect and molecular mechanisms underlying Notch-driven LPS based on our preliminary genomics and lipidomics results, and futher explore therapeutic interventions to treat the murine and human LPS in xenograft mouse models. Results from the proposed work will for the first time uncover the oncogenic function of Notch signaling in adipocytes and adipose tissue, one of the most important metabolic organs in the body. In addition, our transgenic mouse model will represent a unique tool to study the etiology, pathogenesis and treatment of human LPS.

Public Health Relevance

This project aims to explore the signaling mechanisms underlying the pathogenesis of liposarcoma, the most common form of soft-tissue tumors (sarcomas). Recent studies from our team lead to the discovery that aberrant activation of ?Notch? signaling drives the transformation of normal fat cells (adipocytes) into malignant liposarcoma. The proposed work will elucidate how Notch signaling transforms murine and human adipocytes into liposarcoma, and explore therapeutic strategies to treat this malignancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA212609-01A1
Application #
9384493
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Yassin, Rihab R
Project Start
2017-06-13
Project End
2022-05-31
Budget Start
2017-06-13
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$354,563
Indirect Cost
$125,813
Name
Purdue University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Jiang, Chunhui; Cano-Vega, Mario Alberto; Yue, Feng et al. (2017) Dibenzazepine-Loaded Nanoparticles Induce Local Browning of White Adipose Tissue to Counteract Obesity. Mol Ther 25:1718-1729