S-acyl transferase ZDHHC13 modulates tumor microenvironment interactions to suppress metastasis in melanoma models
Hongjin Li, Jianke Lyu, Yu Sun, Chengqian Yin, Yuewen Li, Weiqiang Chen, Suan-Sin Foo, Xianfang Wu, Colin R. Goding, Shuyang Chen
Hongjin Li, Jianke Lyu, Yu Sun, Chengqian Yin, Yuewen Li, Weiqiang Chen, Suan-Sin Foo, Xianfang Wu, Colin R. Goding, Shuyang Chen
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Research Article Immunology Oncology

S-acyl transferase ZDHHC13 modulates tumor microenvironment interactions to suppress metastasis in melanoma models

Abstract

The intratumor microenvironment shapes the metastatic potential of cancer cells and their susceptibility to any immune response. Yet, the nature of the signals within the microenvironment that control anticancer immunity and how they are regulated is poorly understood. Here, using melanoma as a model, we investigate the involvement in metastatic dissemination and the immune-modulatory microenvironment of Protein S-Acyl Transferases as an underexplored class of potential therapeutic targets. We find that ZDHHC13 suppresses metastatic dissemination by palmitoylation of CTNND1, leading to stabilization of E-cadherin. Importantly, ZDHHC13 also reshapes the tumor immune microenvironment by suppressing lysophosphatidylcholine (LPC) synthesis in melanoma cells, leading to inhibition of M2-like tumor-associated macrophages that we show degrade E-cadherin via MMP12 expression. Consequently, ZDHHC13 activity suppresses tumor growth and metastasis in immunocompetent mice. Our study highlights the therapeutic potential of targeting the ZDHHC13–E-cadherin axis and its downstream metabolic and immune-modulatory mechanisms, offering additional strategies to inhibit melanoma progression and metastasis.

Authors

Hongjin Li, Jianke Lyu, Yu Sun, Chengqian Yin, Yuewen Li, Weiqiang Chen, Suan-Sin Foo, Xianfang Wu, Colin R. Goding, Shuyang Chen

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Figure 6

ZDHHC13 reshapes the tumor immune microenvironment.

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ZDHHC13 reshapes the tumor immune microenvironment. (A) 1 × 106 B16 or B...
(A) 1 × 106 B16 or B16 stably expressing ZDHHC13 in 100 μl PBS were subcutaneously injected into the shaved flank of C57/BL6 mice. The t-SNE plot visualization of 10 × single cell transcriptome of 45,481 CD45+ cells sorted from tumors on day 12 was generated by Loupe. Color coded clusters were generated by K-means clustering. Cluster identity was assigned based on the expressions of lineage specific markers. (B) Distribution of cells from each genotype across clusters. (C and D) Macrophages were depleted in C57BL/6 mice through IV injection of clodronate liposomes, given 2 days before tumor inoculation. Three injections will be administered with 3-day intervals between each dose to maintain macrophage depletion. Mice were injected with 1 × 106 B16 melanoma cells, tumor growth were monitored. (E) NOD scid mice were subcutaneously inoculated with 5 × 105 B16F10 in 100 μl PBS mixed with 2 × 105 Bone marrow-derived macrophages (BMDMs). BMDMs were pretreated with IL-4, TGF-β and IL-10 mix (10 ng/ml) for 24 hours to induced M2-like polarization. Tumor growth was recorded. (F) Flow cytometry of tumor-infiltrating macrophages showing M1- and M2-like subsets from tumors in Figure 4D (n = 4). (G) Flow cytometry of lung-infiltrating macrophages showing M1- and M2-like subsets from metastases in Figure 4H (n = 5). All data in this Figure are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, unpaired student’s t test.