Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition.
Amino Acid Transport System y+
/ antagonists & inhibitors
Animals
Antibodies, Monoclonal
/ pharmacology
Apoptosis
Cancer-Associated Fibroblasts
/ drug effects
Carcinoma, Pancreatic Ductal
/ genetics
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Pancreatic Neoplasms
/ genetics
Prognosis
Survival Rate
Tumor Cells, Cultured
Tumor Microenvironment
Xenograft Model Antitumor Assays
Pancreatic Neoplasms
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 07 2021
01 07 2021
Historique:
received:
24
07
2020
revised:
01
03
2021
accepted:
28
04
2021
pubmed:
14
5
2021
medline:
15
12
2021
entrez:
13
5
2021
Statut:
ppublish
Résumé
Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene-silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. SIGNIFICANCE: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.
Identifiants
pubmed: 33980655
pii: 0008-5472.CAN-20-2496
doi: 10.1158/0008-5472.CAN-20-2496
doi:
Substances chimiques
Amino Acid Transport System y+
0
Antibodies, Monoclonal
0
SLC7A11 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3461-3479Informations de copyright
©2021 American Association for Cancer Research.
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