Project Details
Description
PROJECT DESCRIPTION/ABSTRACT
Therapeutically resistant triple negative breast cancer (TNBC) is characterized by mesenchymal features that
facilitate immune evasion and disease progression, resulting in high rates of death from the disease. New
strategies targeting the mesenchymal phenotype to overcome therapeutic resistance are needed. Interactions
between the cytoskeleton of cancer cells and the surrounding extracellular matrix play important roles in initiating
local invasion and metastasis. The resulting mechanical stimuli activate signaling pathways which promote the
transition of non-motile polarized epithelial cells to cells with mesenchymal properties that are able to invade
surrounding tissues and evade immune surveillance, a process termed epithelial to mesenchymal transition
(EMT). Fibrotic stiffening of the non-cellular stroma resulting from extracellular matrix deposition is a common
feature of TNBC and other malignancies that is associated with therapeutic resistance and poor prognosis. How
mechanical stress promotes EMT and cancer progression has not been elucidated.
Ataxia Telangiectasia Mutated and Rad-3 Related (ATR) is best known as a regulator of the DNA damage
response in replicating cells. In our preliminary data, we have found that high ATR protein expression is
associated with reduced progression-free survival in TNBC. We discovered that ATR is post-translationally
upregulated by a deubiquitinating enzyme, USP21, in response to mechanical stress, and that ATR regulates
the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex to promote β-catenin nuclear translocation and
mechanical stress-induced EMT. This new role for ATR in mechanical stress and EMT is independent of ATR’s
established function in regulating the DNA damage response. In a clinical trial of anti-PD-1 immunotherapy for
advanced TNBC, high ATR levels in biopsy specimens was correlated with EMT and reduced responsiveness.
ATR inhibition could promote mesenchymal to epithelial transition and anti-tumor immunity in vivo. We
hypothesize that ATR regulates the LINC complex following mechanical stress to promote β-catenin mediated
EMT, immune evasion, and TNBC progression. We will test this hypothesis through three specific aims. Aim 1
will examine the impact of mechanical stress on ATR deubiquitination and the LINC complex; Aim 2 will evaluate
how ATR influences β-catenin pathway activation and EMT; Aim 3 will investigate the role of ATR-SUN2 in
stiffness and EMT associated immune evasion.
Status | Active |
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Effective start/end date | 8/1/23 → 7/31/24 |
Funding
- National Cancer Institute: $369,203.00
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