Abstract 2701: EREG reprograms M2-tumor-associated macrophage and suppresses colorectal cancer cell proliferation and migration
Authors: Ah-Ran Yu, Seijong Kim, Yelin Jeong, Hye Kyung Hong, Yong Jae Shin, Yong Beom Cho
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) represents a common malignancy within the digestive system, linked to significant morbidity and mortality rates. Tumors exert diverse effects on immune modulation, facilitating progression and metastasis. Amid the abundant immune cell populace within the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a pivotal role. M2-type TAMs actively foster tumor growth and engage in immune suppression by fostering angiogenesis and tissue restructuring. In a previous study, we analyzed single-cell RNA-sequencing (scRNA-seq) data derived from colorectal cancer patients. We observed an enrichment of the secreted phosphoprotein 1 (SPP1)+ macrophage fraction in both the tumor core and border when compared to normal tissues. Additionally, epiregulin (EREG), an epidermal growth factor receptor (EGFR) ligand, was found to be upregulated in SPP1+ macrophages, correlating with tumor growth and metastatic tendencies. Research on EREG is important because it has been found to play a significant role in cancer progression, including colorectal cancer. Understanding the mechanisms by which EREG contributes to tumor growth and metastasis can provide valuable insights into the development of targeted therapies for cancer treatment. Our hypothesis centered around the impact of EREG from TAMs on tumor progression. To identify TAM-specific EREG and its functional significance, we isolated tumor-associated macrophages from CT26 (mouse colorectal carcinoma)-bearing tumors and cultured them with conditioned and normal mediums. Subsequently, we examined EREG expression at the gene level using quantitative PCR. Our findings indicated significantly higher levels of EREG in the conditioned medium compared to the normal medium, suggesting an association between EREG and cancer cells. Remarkably, our investigation also confirmed that EREG has the capacity to reshape macrophage signatures. Notably, the surface marker CD206, characteristic of M2 macrophages, exhibited a significant decrease, while iNOS, a marker for M1 macrophages, showed an increase upon EREG depletion. We evaluated the interaction between CT26 cancer cells and TAMs using indirect co-culture methods. EREG-depleted TAMs were plated in the top chamber, while CT26 colorectal cancer cells were seeded at the bottom. Our results validated that knocking down EREG in TAMs not only hindered the proliferation of cancer cells but also affected the behavior of TAMs. Additionally, the reduced EREG expression in TAMs hindered the migration of cancer cells. These findings strongly suggest that targeting EREG could effectively restrain the growth and metastasis of colorectal cancer cells by reprogramming macrophage polarization in the TME. Consequently, this indicates its potential as a promising therapeutic target in colorectal cancer. Citation Format: Ah-Ran Yu, Seijong Kim, Yelin Jeong, Hye Kyung Hong, Yong Jae Shin, Yong Beom Cho. EREG reprograms M2-tumor-associated macrophage and suppresses colorectal cancer cell proliferation and migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2701.