Targeting acidic pre-metastatic niche in lungs by pH low insertion peptide and its utility for anti-metastatic therapy

Abstract

Dysregulated extracellular pH, the universal feature of tumor, works as an evolutional force to drive dissemination of tumor cells. It is well-established that tumor acidity is associated with tumor growth and metastasis. However, the pH of pre-metastatic niche remains unclear. We hypothesized that primary tumor cells remotely prime acidity in secondary organ to achieve metastatic colonization. Herein, we demonstrated that the pH responsive probe pH Low Insertion Peptide (pHLIP) was notably accumulated in pre-metastatic lungs of 4T1.2 breast tumor-bearing mice. The pHLIP-targeted lungs showed high amounts of lactate and overexpressed glycolysis-related proteins. Pharmacological inhibition of glycolysis suppressed the lung acidification induced by 4T1.2 cancer cell culture supernatant and delayed subsequent metastatic burden of disseminated tumor cells. In the acidic lungs, pHLIP was primarily localized in alveolar type 2 cells which strongly expressed glycolysis-related proteins. 4T1.2-derived extracellular vesicles expressed some of the glycolysis-related proteins, and their administration increased pHLIP accumulation and glycolytic enhancement in lungs. pHLIP-conjugated dexamethasone effectively attenuated lung metastatic burden by disrupting pro-inflammatory response in the acidic lungs. From these results, targeting the metastasis-supporting microenvironment by pHLIP technology creates possibility to identify pre-metastatic organ and prevent metastatic recurrence.

Aiming the magic bullet: targeted delivery of imaging and therapeutic agents to solid tumors by pHLIP peptides

“…Within the TME, cancer cells, CAFs, TAMs and mMDSC are marked by pHLIP ( Sahraei et al, 2019 ; Moshnikova et al, 2022a ; Visca et al, 2022 ). In addition to primary tumors, satellites near the primary tumor, pre-metastatic niche and micro-metastases in distant organs have been shown to be well targeted by pHLIP peptides ( Segala et al, 2009 ; Reshetnyak et al, 2011 ; Cruz-Monserrate et al, 2014 ; Adochite et al, 2016 ; Rohani et al, 2019 ; Crawford et al, 2020 ; Gillies, 2021 ; Matsui et al, 2023 ).…”

“…The future, as has been often noted, is difficult to predict, but the rapid growth of the field and the diversity of promising approaches inspire optimism that benefits to patients are likely to emerge. The pHLIP technology may find applications not only in tumor imaging and treatment, but also in the targeting (and treatment) of inflamed and fibrotic tissues ( Price et al, 2019 ; Visca et al, 2022 ; Matsui et al, 2023 ), atherosclerosis ( Zhang et al, 2022 ), ischemic stroke ( Ye et al, 2023 ) and ischemic myocardium ( Sosunov et al, 2013 ; Hulikova et al, 2022 ). These diseased states are associated with elevated levels of acidity due to the presence of overactivated immune cells and/or due to hypoxia developed in diseased tissues.…”