Our long-term goals are to define the molecular mechanisms by which fascin controls cancer metastasis and progression. Cancer metastasis involves the dissemination of cancer cells from primary tumor to distant organ, and the expansion of disseminated metastatic cells to form secondary tumor. It has been well established that the actin cytoskeleton is frequently dysregulated to promote cancer cell motility, invasiveness during metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton in cancer metastasis is largely unexplored. Fascin is the most frequently overexpressed actin binding protein in metastatic cancer, and its overexpression is uniformly associated with metastatic disease, aggressive clinical course and shorter survival across different cancer types. It is generally thought that fascin drives cancer metastasis by strengthening the actin cytoskeleton and promoting cell motility. In preliminary studies conducted in NSCLC models, we discovered a novel role for fascin in promoting metastatic colonization and expansion and augmenting cancer cell stemness by remodeling mitochondrial actin filaments. We propose that fascin enhances the self-renewal of cancer stem-like cell and metastatic expansion through a novel fascin-mitochondria-AMPK-YAP/TAZ pathway. We will build on these exciting preliminary findings to investigate the functional role of fascin- mediated remodeling of mitochondrial actin filaments in Aim 1. We will then define the role of the AMPK- YAP/TAZ pathway in fascin-mediated augmentation of cancer cell stemness in Aim 2.
In Aim 3 we will determine the novel mitochondrial role of fascin and mitochondrial actin filaments in fascin-mediated NSCLC metastasis, and will explore the feasibility to inhibit cancer cell stemness and metastatic recurrence by targeting fascin. The success of proposed studies will cause a paradigm-shift in our understanding of the dysregulated actin cytoskeleton in metastatic progression, and will potentially provide novel avenues to prevent NSCLC metastatic recurrence.

Public Health Relevance

This project investigates the basic mechanisms underlying the regulation of mitochondria and metabolic reprograming during metastasis, which accounts for more than 90% of cancer-related death. The anticipated results from this proposal will significantly advance our understanding of cancer metastasis, and potentially provide novel strategy for preventing metastatic progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA233844-01
Application #
9637985
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Espey, Michael G
Project Start
2018-12-04
Project End
2023-11-30
Budget Start
2018-12-04
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033