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Transformable ECM Deprivation System Effectively Suppresses Renal Cell Carcinoma by Reversing Anoikis Resistance and

Lu Wang1,2, Cong Li1,2, Jiaqi Wang1,2

  • 1NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China.

Advanced Materials (Deerfield Beach, Fla.)
|August 25, 2022
PubMed

Insights

A novel ECM deprivation system (EDS) targets fibronectin (FN) in renal cell carcinoma. This system reverses anoikis resistance and enhances chemotherapy efficacy by inhibiting FN signaling pathways.

Area of Science:

  • Biomedical Engineering
  • Cancer Biology
  • Drug Delivery

Background:

  • Extracellular matrix (ECM) plays a critical role in tumor progression, promoting anoikis resistance and cell adhesion-mediated drug resistance (CAM-DR).
  • Fibronectin (FN), a key ECM component, directly influences these resistance mechanisms, presenting a potential therapeutic target.
  • Renal cell carcinoma (RCC) progression is significantly impacted by ECM-mediated signaling.

Purpose of the Study:

  • To develop an ECM deprivation system (EDS) for targeting fibronectin in renal cell carcinoma.
  • To investigate the potential of EDS in reversing anoikis resistance and enhancing chemotherapy sensitivity.
  • To evaluate the therapeutic efficacy of EDS in preclinical models of RCC.

Main Methods:

  • Development of a self-assembly peptide-based EDS designed to target and form nanofibers within the ECM.
  • Assessment of EDS's ability to target FN, reverse anoikis resistance by inhibiting the FN signaling pathway (FAK phosphorylation), and act as a drug-loading platform.
  • In vitro and in vivo evaluation of EDS, alone and in combination with doxorubicin (DOX), for its effects on RCC cell viability, tumor growth, and metastasis.

Main Results:

  • The developed EDS effectively targets FN and forms stable nanofibers in the ECM.
  • EDS significantly reverses anoikis resistance in RCC cells by inhibiting FAK phosphorylation, a key regulator of the FN signaling pathway.
  • EDS demonstrates synergistic effects with doxorubicin (DOX), enhancing chemotherapy sensitivity and effectively suppressing tumor growth and metastasis in vivo.

Conclusions:

  • The innovative ECM deprivation system (EDS) effectively targets fibronectin, inhibiting tumor-promoting ECM effects.
  • EDS shows promise in reversing anoikis resistance and enhancing chemo-drug sensitivity in renal cell carcinoma.
  • This approach offers a novel strategy for cancer therapy by targeting the tumor microenvironment and improving chemotherapeutic outcomes.
Keywords:
anoikis resistancecell adhesion-mediated drug resistancechemotherapy-sensitizersextracellular matricesself-assembly

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