bims-lymeca Biomed News
on Lysosome metabolism in cancer
Issue of 2023–08–06
two papers selected by
Harilaos Filippakis, University of New England
  1. Intra-Lysosomal Peptide Assembly for the High Selectivity Index against Cancer.
  2. Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy.
  1. J Am Chem Soc. 2023 Jul 31.
    Intra-Lysosomal Peptide Assembly for the High Selectivity Index against Cancer.
    Batakrishna Jana, Seongeon Jin, Eun Min Go, Yumi Cho, Dohyun Kim, Sangpil Kim, Sang Kyu Kwak, Ja-Hyoung Ryu.
      Lysosomes remain powerful organelles and important targets for cancer therapy because cancer cell proliferation is greatly dependent on effective lysosomal function. Recent studies have shown that lysosomal membrane permeabilization induces cell death and is an effective way to treat cancer by bypassing the classical caspase-dependent apoptotic pathway. However, most lysosome-targeted anticancer drugs have very low selectivity for cancer cells. Here, we show intra-lysosomal self-assembly of a peptide amphiphile as a powerful technique to overcome this problem. We designed a peptide amphiphile that localizes in the cancer lysosome and undergoes cathepsin B enzyme-instructed supramolecular assembly. This localized assembly induces lysosomal swelling, membrane permeabilization, and damage to the lysosome, which eventually causes caspase-independent apoptotic death of cancer cells without conventional chemotherapeutic drugs. It has specific anticancer effects and is effective against drug-resistant cancers. Moreover, this peptide amphiphile exhibits high tumor targeting when attached to a tumor-targeting ligand and causes significant inhibition of tumor growth both in cancer and drug-resistant cancer xenograft models.
    DOI:  https://doi.org/10.1021/jacs.3c04467
  2. J Exp Clin Cancer Res. 2023 Aug 04. 42(1): 192
    Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy.
    Jing Ma, Ruijuan Ma, Xueke Zeng, Liming Zhang, Jianing Liu, Wei Zhang, Tao Li, Hanjing Niu, Guochen Bao, Chaojie Wang, Peng George Wang, Jiajia Wang, Xia Li, Taotao Zou, Songqiang Xie.
       BACKGROUND: Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor immunity in tumours and macrophages is poorly understood and the underlying mechanisms are elusive. The present study aimed to explore a synergistic strategy to dismantle the immunosuppressive microenvironment of tumours and metallodrugs discovery by using the herent metabolic plasticity.
    METHODS: Naphplatin was prepared by coordinating an active alkaline moiety to cisplatin, which can regulate the lysosomal functions. Colorectal carcinoma cells were selected to perform the in vivo biological assays. Blood, tumour and spleen tissues were collected and analyzed by flow cytometry to further explore the relationship between anti-tumour activity and immune cells. Transformations of bone marrow derived macrophage (BMDM) and M2-BMDM to the M1 phenotype was confirmed after treatment with naphplatin. The key mechanisms of lysosome-mediated mucolipin-1(Mcoln1) and mitogen-activated protein kinase (MAPK) activation in M2 macrophage polarization have been unveiled. RNA sequencing (RNA-seq) was used to further explore the key mechanism underlying high-mobility group box 1(HMGB1)-mediated Cathepsin L(CTSL)-lysosome function blockade.
    RESULTS: We demonstrated that naphplatin induces divergent lysosomal metabolic programs and reprograms macrophages in tumor cells to terminate the vicious tumour-associated macrophages (TAMs)-MDSCs-Treg triangle. Mechanistically, macrophages treated with naphplatin cause lysosome metabolic activation by triggering Ca2+ release via Mcoln1, which induces the activation of p38 and nuclear factor-κB (NF-κB) and finally results in polarizing M2 macrophages. In contrast, HMGB1-mediated lysosome metabolic blockade in cancer cells is strongly linked to antitumor effects by promoting cytoplasmic translocation of HMGB1.
    CONCLUSIONS: This study reveals the crucial strategies of macrophage-based metallodrugs discovery that are able to treat both immunologically "hot" and "cold" cancers. Different from traditional platinum-based antitumour drugs by inhibition of DNAs, we also deliver a strong antitumour strategy by targeting lysosome to induce divergent metabolic programs in macrophages and tumours for cancer immunotherapy.
    DOI:  https://doi.org/10.1186/s13046-023-02768-0
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