Theranostics 2021; 11(5):2182-2200. doi:10.7150/thno.53102 This issue Cite

Research Paper

Silencing PCBP2 normalizes desmoplastic stroma and improves the antitumor activity of chemotherapy in pancreatic cancer

Yuanke Li1,§, Zhen Zhao1,§, Chien-Yu Lin1, Yanli Liu1, Kevin F. Staveley-OCarroll2, Guangfu Li2, Kun Cheng1,✉

1. Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
2. Department of Surgery, School of Medicine, University of Missouri, One Hospital Drive, Columbia, MO 65212
§ These authors contributed equally to this work.

Citation:
Li Y, Zhao Z, Lin CY, Liu Y, Staveley-OCarroll KF, Li G, Cheng K. Silencing PCBP2 normalizes desmoplastic stroma and improves the antitumor activity of chemotherapy in pancreatic cancer. Theranostics 2021; 11(5):2182-2200. doi:10.7150/thno.53102. https://www.thno.org/v11p2182.htm
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Abstract

Graphic abstract

Rationale: Dense desmoplastic stroma is a fundamental characteristic of pancreatic ductal adenocarcinoma (PDAC) and comprises up to 80% of the tumor mass. Type I collagen is the major component of the extracellular matrix (ECM), which acts as a barrier to impede the delivery of drugs into the tumor microenvironment. While the strategy to deplete PDAC stroma has failed in clinical trials, normalization of the stroma to allow chemotherapy to kill the tumor cells in the “nest” could be a promising strategy for PDAC therapy. We hypothesize that silencing the poly(rC)-binding protein 2 (αCP2, encoded by the PCBP2 gene) leads to the destabilization and normalization of type I collagen in the PDAC stroma.

Methods: We develop a micro-flow mixing method to fabricate a peptide-based core-stabilized PCBP2 siRNA nanocomplex to reverse the accumulation of type I collagen in PDAC tumor stroma. Various in vitro studies were performed to evaluate the silencing activity, cellular uptake, serum stability, and tumor penetration of the PCBP2 siRNA nanocomplex. We also investigated the penetration of small molecules in stroma-rich pancreatic cancer spheroids after the treatment with the PCBP2 siRNA nanocomplex. The anti-tumor activity of the PCBP2 siRNA nanocomplex and its combination with gemcitabine was evaluated in an orthotopic stroma-rich pancreatic cancer mouse model.

Results: Silencing the PCBP2 gene using siRNA reverses the accumulation of type I collagen in human pancreatic stellate cells (PSCs) and mouse NIH 3T3 fibroblast cells. The siRNA nanocomplex significantly reduces ECM production and enhances drug penetration through desmoplastic tumor stroma. The combination of gemcitabine with the PCBP2 siRNA nanocomplex markedly suppresses the tumor progression in a desmoplastic PDAC orthotopic mouse model.

Conclusion: This approach provides a new therapeutic avenue to improve the antitumor efficacy of PDAC therapies by normalizing tumor stroma using the PCBP2 siRNA nanocomplex.

Keywords: PCBP2, siRNA, pancreatic cancer, tumor stroma, nanocomplex


Citation styles

APA
Li, Y., Zhao, Z., Lin, C.Y., Liu, Y., Staveley-OCarroll, K.F., Li, G., Cheng, K. (2021). Silencing PCBP2 normalizes desmoplastic stroma and improves the antitumor activity of chemotherapy in pancreatic cancer. Theranostics, 11(5), 2182-2200. https://doi.org/10.7150/thno.53102.

ACS
Li, Y.; Zhao, Z.; Lin, C.Y.; Liu, Y.; Staveley-OCarroll, K.F.; Li, G.; Cheng, K. Silencing PCBP2 normalizes desmoplastic stroma and improves the antitumor activity of chemotherapy in pancreatic cancer. Theranostics 2021, 11 (5), 2182-2200. DOI: 10.7150/thno.53102.

NLM
Li Y, Zhao Z, Lin CY, Liu Y, Staveley-OCarroll KF, Li G, Cheng K. Silencing PCBP2 normalizes desmoplastic stroma and improves the antitumor activity of chemotherapy in pancreatic cancer. Theranostics 2021; 11(5):2182-2200. doi:10.7150/thno.53102. https://www.thno.org/v11p2182.htm

CSE
Li Y, Zhao Z, Lin CY, Liu Y, Staveley-OCarroll KF, Li G, Cheng K. 2021. Silencing PCBP2 normalizes desmoplastic stroma and improves the antitumor activity of chemotherapy in pancreatic cancer. Theranostics. 11(5):2182-2200.

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