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
View: Text | PDF
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

×

Figure 7

SMPD2 is a downstream of ZDHHC13 to induce M2-like TAM polarization.

Options: View larger image (or click on image) Download as PowerPoint
SMPD2 is a downstream of ZDHHC13 to induce M2-like TAM polarization. (A)...
(A) RNA-seq analysis of B16 cells with or without ZDHHC13 expression showing genes involved in LPC and SM metabolism. (B) IHC of SMPD2 in melanoma tissue array; staining quantified in ImageJ and correlated by Pearson’s analysis. (C) Analysis of survival of patients with Melanoma based on SMPD2 expression (cutoff = 50%) calculated by GEPIA2. All patients in the TCGA melanoma study were divided according to the expression level of SMPD2 (higher or lower level than median expression value of all patients). (D) Validation of Smpd2 knockdown in B16 cells, and quantification of SM and LPC levels by using Abcam SM and LPC assay kit (Abcam ab138877 and ab273332), respectively. (E–G) 2 × 105 cells generated in D in 100 μl PBS were injected into C57BL/6 mice via the tail vein. Pulmonary metastases (E and F) and lung H&E staining (E) were assessed 14 days after tumor cell injection. Mouse survival was recorded (G) (n = 6). Scale bar: 185 μm. (H) Flow cytometry analysis of ARG1+ M2-like macrophages in lungs from mice in E (n = 3). All data in this Figure are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, unpaired Student’s t test.