Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense fibrotic stroma, which contributes to tumor growth, metastasis, and drug resistance. During tumorigenesis, quiescent pancreatic stellate cells (PSCs) are activated and become major contributors to fibrosis, by increasing growth factor signaling and extracellular matrix deposition. The p53 tumor suppressor is known to restrict tumor initiation and progression through cell autonomous mechanisms including apoptosis, cell cycle arrest, and senescence. There is growing evidence that stromal p53 also exerts anti-tumor activity by paracrine mechanisms, though a role for stromal p53 in PDAC has not yet been described. Here, we demonstrate that activation of stromal p53 exerts anti-tumor effects in PDAC. We show that primary cancer-associated PSCs (caPSCs) isolated from human PDAC express wild-type p53, which can be activated by the Mdm2 antagonist Nutlin-3a. Our work reveals that p53 acts as a major regulator of PSC activation and as a modulator of PDAC fibrosis. In vitro, p53 activation by Nutlin-3a induces profound transcriptional changes, which reprogram activated PSCs to quiescence. Using immunofluorescence and lipidomics, we have also found that p53 activation induces lipid droplet accumulation in both normal and tumor-associated fibroblasts, revealing a previously undescribed role for p53 in lipid storage. In vivo, treatment of tumor-bearing mice with the clinical form of Nutlin-3a induces stromal p53 activation, reverses caPSCs activation, and decreases fibrosis. All together our work uncovers new functions for stromal p53 in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) represents the third leading cause of cancerrelated deaths in the United States, with an overall 5-year survival rate of ~9% [1]
Our work reveals that Nutlin-3a induces p53 activation in both murine and human Cancer-associated PSCs (caPSCs) and reprograms these cells towards quiescence
This demonstrates that caPSCs express functional p53 and that the p53 transcriptional pathway is robustly activated by Nutlin-3a
Summary
Pancreatic ductal adenocarcinoma (PDAC) represents the third leading cause of cancerrelated deaths in the United States, with an overall 5-year survival rate of ~9% [1]. PDAC is characterized by the formation of an extremely dense fibrotic stroma ( called desmoplasia) that surrounds the cancer cells and represents up to 90% of the tumor volume [2] This reactive stroma has been implicated as a major facilitator of tumor growth, metastasis and drug resistance [3]. PSCs are activated by pro-inflammatory cytokines, growth factors, and other oxidative and/or metabolic stresses, and transdifferentiate into myofibroblast-like cells [7] This activation is accompanied by a loss of cytoplasmic lipid droplets, increased expression of the cytoskeletal protein α-smooth muscle actin (αSMA), and an increase in proliferation [8]. Cancer-associated PSCs (caPSCs) establish fibrosis via the synthesis of excessive ECM proteins (i.e. collagen, fibronectin, laminin) and ECM remodeling proteins (matrix metalloproteinases and their inhibitors) This dense ECM compresses intra-tumoural vasculature, causing hypoxia and impeding drug delivery to the tumor [9,10]. CaPSCs secrete growth factors and cytokines that sustain their own activation and promote cancer cell growth, survival and migration [11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
