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ATF4 regulates CCL2 expression to promote endometrial cancer growth by controlling macrophage infiltration
Bin Liu1, Pingping Chen1, Di Xi1
1Departments of Assisted Reproduction, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China.
Abstract:
Activating transcription factor 4 (ATF4), an endoplasmic reticulum stress-inducible transcription factor, plays important roles in cancer progression and resistance to therapy. However, no report is available about its roles in endometrial cancer (EC). In this study, we found that ATF4 is commonly expressed in EC cell lines. Loss-of-function studies in two EC cell lines showed that ATF4 knockdown suppresses tumor growth of EC in vivo without influencing cell proliferation in vitro. And xenograft tumors derived from ATF4-knockdown cells had reduced M2 macrophage infiltration. In clinical specimens, ATF4-high expressing tumors indeed contained more macrophage infiltration compared to those with lower ATF4 expression. Moreover, we identified that ATF4-mediated chemokine CCL2 expression ultimately results in macrophage infiltration and tumor growth of EC. Taken together, our findings suggest that ATF4 contributes to tumor growth of EC by promoting CCL2 and subsequent recruitment of macrophage, and that ATF4/CCL2 axis might be a potential therapeutic target for EC.
Insights
Activating transcription factor 4 (ATF4) promotes endometrial cancer (EC) growth by increasing macrophage infiltration via CCL2. Targeting the ATF4/CCL2 pathway may offer new therapeutic strategies for EC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Activating transcription factor 4 (ATF4) is an endoplasmic reticulum stress-inducible factor implicated in cancer progression.
- The role of ATF4 in endometrial cancer (EC) remains unexplored.
- Understanding novel molecular mechanisms driving EC is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of ATF4 in endometrial cancer (EC) progression.
- To elucidate the underlying molecular mechanisms by which ATF4 influences EC.
- To evaluate the potential of the ATF4/CCL2 axis as a therapeutic target in EC.
Main Methods:
- Expression analysis of ATF4 in EC cell lines and clinical specimens.
- In vivo and in vitro loss-of-function studies using ATF4 knockdown in EC cell lines.
- Assessment of tumor growth, M2 macrophage infiltration, and CCL2 expression in xenograft models.
- Correlation analysis between ATF4 expression and macrophage infiltration in clinical EC samples.
Main Results:
- ATF4 is commonly expressed in EC cell lines and its knockdown suppresses tumor growth in vivo.
- ATF4 knockdown reduced M2 macrophage infiltration in xenograft tumors.
- ATF4-high tumors exhibited increased macrophage infiltration compared to ATF4-low tumors.
- ATF4 promotes EC tumor growth by mediating CCL2 expression, leading to macrophage recruitment.
Conclusions:
- ATF4 plays a significant role in promoting endometrial cancer (EC) tumor growth.
- The ATF4/CCL2 signaling pathway drives macrophage infiltration, contributing to EC progression.
- Targeting the ATF4/CCL2 axis presents a promising therapeutic strategy for endometrial cancer.
