Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin β3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery

Abstract

Epithelial-mesenchymal transition (EMT) is closely associated with the development of drug resistance. Lipid metabolism plays an important role in EMT. This work was to study the cholesterol-lowering drug simvastatin for reversing EMT-associated resistance to chemotherapy via lipid metabolism.Methods: The combination of simvastatin and paclitaxel was used to overcome the EMT-associated drug resistance. For dual-action on both cancer cells and tumor-associated macrophages (TAM), the tumor microenvironment-activatable multifunctional liposomes were developed for drug codelivery. The liposomes were modified with a hairpin-structured, activatable cell-penetrating peptide that is specifically responsive to the tumor-associated protease legumain.Results: It was revealed simvastatin can disrupt lipid rafts (cholesterol-rich domains) and suppress integrin-β3 and focal adhesion formation, thus inhibiting FAK signaling pathway and re-sensitizing the drug-resistant cancer cells to paclitaxel. Furthermore, simvastatin was able to re-polarize tumor-associated macrophages (TAM), promoting M2-to-M1 phenotype switch via cholesterol-associated LXR/ABCA1 regulation. The repolarization increased TNF-α, but attenuated TGF-β, which, in turn, remodeled the tumor microenvironment and suppressed EMT. The liposomal formulation achieved enhanced treatment efficacy.Conclusion: This study provides a promising simvastatin-based nanomedicine strategy targeting cholesterol metabolism to reverse EMT and repolarize TAM to treat drug-resistant cancer. The elucidation of the molecular pathways (cholesterol/lipid raft/integrin β3/FAK and cholesterol-associated LXR/ABCA1 regulation) for anti-EMT and the new application of simvastatin should be of clinical significance.

Reprogramming Tumor Associated Macrophages toward M1 Phenotypes with Nanomedicine for Anticancer Immunotherapy

“…On this basis, Huang and co‐workers found that the simvastatin‐loaded nanoparticles or liposomes could efficiently re‐educate TAMs toward M1 phenotypes, and expand their antitumor application in several tumor models. [ 51 ] They developed a legumain‐activable liposome loading simvastatin and cytotoxic paclitaxel, which effectively promoted the reprogramming of TAMs to M1 macrophages. The repolarization displayed increased TNF‐α and attenuated TGF‐β, thereby remodeling the antitumor TME and synergizing with paclitaxel to treat drug resistant A549/T nonsmall cell lung cancer (NSCLC) model.…”

Nanomaterials as Inhibitors of Epithelial Mesenchymal Transition in Cancer Treatment

“…Different nanomaterials have been exploited to deliver synthetic chemotherapeutics and chemicals inside cancer cells reverting EMT and chemoresistance, and prevent metastasis in a plethora of tumor types [68][69][70][71][72][73][74][75][76][77][78].…”

Rafting Down the Metastatic Cascade: The Role of Lipid Rafts in Cancer Metastasis, Cell Death, and Clinical Outcomes

“…Lipid raft disruption has been shown to attenuate EMT in cancer. One study found that disrupting lipid rafts with simvastatin suppressed integrin-β3/FAK signaling, reversing EMT and EMT-associated paclitaxel resistance in non-small cell lung cancer (NSCLC) cells (30). Another study found that nystatin, a cholesterol sequestering agent, suppressed EMT markers in gastric cancer cells (31).…”