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 4

ZDHHC13 suppress melanoma growth and metastasis in immunocompetent mouse.

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ZDHHC13 suppress melanoma growth and metastasis in immunocompetent mouse...
(A and B) 2 × 105 Ctnnd1-depleted B16 stably expressing C618S CTNND1 and ZDHHC13 in 100 μl PBS were injected into NOD scid mice (A) or C57BL/6 mice (B) via the tail vein. Pulmonary metastases were assessed 14 days after tumor cell injection (n = 6). (C) Schematic model: ZDHHC13-mediated palmitoylation of CTNND1 suppresses melanoma progression by stabilizing E-cadherin and modulating immune cell function. (D–G) 1 × 106 B16 or B16 stably expressing ZDHHC13 in 100 μl PBS were subcutaneously injected into the shaved flank of C57BL/6 mice. Tumor growth, weight (n = 4) and mouse survival (n = 5) were assessed. (H–K) 2 × 105 B16 or B16 stably expressing ZDHHC13 in 100 μl PBS were injected into C57BL/6 mice via the tail vein. Pulmonary metastases (H and I) and lung H&E staining (J) were assessed 14 days after tumor cell injection. Mouse survival was recorded (K) (n = 6). Scale bar: 185 μm. (L–M) Representative locally induced melanoma sections and survival curve and of indicated mice. Scale bar: 100 μm. (N) Tumor metastasis from a Tyr-re/BrafV600E/Pten–/– mouse (day 40 after Tam injection) and a Tyr-Cre/BrafV600E/Pten–/– +Tg-ZDHHC13 mouse (day 55 after Tam injection). (O) Comparison of number of lung metastases visible on the surface of the lungs in indicated mice. All data in this Figure are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, unpaired student’s t test.