Tumor-Derived Exosomal Protein Tyrosine Phosphatase Receptor Type O Polarizes Macrophage to Suppress Breast Tumor Cell Invasion and Migration.

Hongmei Dong,Xiao Xiong,Kai Li,Yexi Chen,Yusheng Lin,Jiehua Zheng,Chaoyu Xie,Yong Li,Hao Zhang,Yuchen Jiang,Xijiao Pang,Xiurong Ke

doi:10.3389/fcell.2021.703537

Abstract

Tumor-derived exosomes, containing multiple nucleic acids and proteins, have been implicated to participate in the interaction between tumor cells and microenvironment. However, the functional involvement of phosphatases in tumor-derived exosomes is not fully understood. We and others previously demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) acts as a tumor suppressor in multiple cancer types. In addition, its role in tumor immune microenvironment remains elusive. Bioinformatical analyses revealed that PTPRO was closely associated with immune infiltration, and positively correlated to M1-like macrophages, but negatively correlated to M2-like macrophages in breast cancer tissues. Co-cultured with PTPRO-overexpressing breast cancer cells increased the proportion of M1-like tumor-associated macrophages (TAMs) while decreased that of M2-like TAMs. Further, we observed that tumor-derived exosomal PTPRO induced M1-like macrophage polarization, and regulated the corresponding functional phenotypes. Moreover, tumor cell-derived exosomal PTPRO inhibited breast cancer cell invasion and migration, and inactivated STAT signaling in macrophages. Our data suggested that exosomal PTPRO inhibited breast cancer invasion and migration by modulating macrophage polarization. Anti-tumoral effect of exosomal PTPRO was mediated by inactivating STAT family in macrophages. These findings highlight a novel mechanism of tumor invasion regulated by tumor-derived exosomal tyrosine phosphatase, which is of translational potential for the therapeutic strategy against breast cancer.

Highlights

Breast cancer, the most common malignancy among women worldwide, is famous for its high mortality with a large number of patients developing recurrence and metastasis (Oskarsson et al, 2011; Sung et al, 2021)
We showed that phosphatase receptor type O (PTPRO) plays a role in immune infiltration in breast cancer
Protein tyrosine phosphatase receptor type O has been recognized as a tumor suppressor in multiple cancer types (Motiwala et al, 2004; You et al, 2012; Dong et al, 2017a)

Summary

Introduction

The most common malignancy among women worldwide, is famous for its high mortality with a large number of patients developing recurrence and metastasis (Oskarsson et al, 2011; Sung et al, 2021). Despite exciting progress in the development of novel therapeutic strategies, such as targeted therapy and immunotherapy, the therapeutic outcome is still unsatisfied and the prognosis remains poor for the patients with metastasis, who have only 26% of estimated 5-year survival (Sambi et al, 2019). There is an urgent need to understand and tackle breast cancer metastasis. Metastasis is a multi-step process including the migration and invasion of cancer cells, subsequent proliferation, and colonization in distant organs (Steeg, 2016). It has been well established that the tumor microenvironment (TME) plays an important role in breast cancer cell invasion and metastasis (Cacho-Diaz et al, 2020). The molecular mechanisms underlying this process are still poorly understood

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