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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Tumoral IL-10-activated SHP2 in macrophages promotes mammary carcinoma progression
Jian Gao1, Zhixiu Chen1, Yixuan Wang1
1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Abstract:
The Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is a non-receptor tyrosine phosphatase and acts as a convergent node for oncogenic cell-signaling cascades. SHP2 has been recognized as a breakthrough anti-tumor therapeutic target. However, it is still elusive for the role of SHP2 in manipulating tumor microenvironment for malignancy. Here, we found that SHP2 activation in tumor-associated macrophages (TAMs) paralleled mammary carcinoma progression. Co-culture system and human breast cancer specimens also showed high levels of phosphorylated SHP2 in macrophages. Conditional SHP2 knockout or pharmacological SHP2 inhibition blocked mammary carcinoma growth and reduced metastasis. More importantly, tumor-derived IL-10 induced SHP2 phosphorylation in macrophages upon the tumor-macrophage interaction. SHP2 activation rendered macrophages an immunosuppressive phenotype and attenuated their responsiveness to type I interferon. IL-10 deficiency in mammary carcinoma cells caused tumor regression, which was accompanied by the reduction of SHP2 activation in TAMs. These findings suggest a protumorigenic role of SHP2 in the crosstalk between macrophages and mammary carcinoma cells in tumor microenvironments and reveal that targeting SHP2 in macrophages could be a therapeutic approach to improve anticancer therapy.
Insights
Targeting SHP2 (Src homology 2 domain-containing tyrosine phosphatase 2) in tumor-associated macrophages can combat mammary carcinoma. SHP2 activation promotes tumor growth and immunosuppression within the tumor microenvironment.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- SHP2 (Src homology 2 domain-containing tyrosine phosphatase 2) is a key regulator in oncogenic signaling pathways.
- Its role in modulating the tumor microenvironment and promoting malignancy remains incompletely understood.
- SHP2 is recognized as a promising therapeutic target for anti-tumor strategies.
Purpose of the Study:
- To investigate the role of SHP2 in tumor-associated macrophages (TAMs) during mammary carcinoma progression.
- To elucidate the mechanism by which SHP2 activation influences the tumor microenvironment.
- To evaluate the therapeutic potential of targeting SHP2 in TAMs for cancer treatment.
Main Methods:
- Utilized co-culture systems and analyzed human breast cancer specimens.
- Employed conditional SHP2 knockout and pharmacological SHP2 inhibition in mouse models.
- Investigated the effect of tumor-derived IL-10 on SHP2 phosphorylation in macrophages.
Main Results:
- SHP2 activation in TAMs correlated with mammary carcinoma progression and was elevated in human breast cancer specimens.
- SHP2 inhibition or knockout significantly reduced tumor growth and metastasis.
- Tumor-derived IL-10 induced SHP2 phosphorylation in TAMs, leading to an immunosuppressive phenotype and reduced responsiveness to type I interferon.
- IL-10 deficiency resulted in tumor regression and decreased SHP2 activation in TAMs.
Conclusions:
- SHP2 plays a protumorigenic role in the crosstalk between TAMs and mammary carcinoma cells within the tumor microenvironment.
- Targeting SHP2 in macrophages represents a potential therapeutic strategy to enhance anticancer therapies.
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