ADAM17-mediated EGFR ligand shedding directs macrophage-promoted cancer cell invasion

Abstract

Macrophages in the tumor microenvironment have a significant impact on tumor progression.Depending on the signaling environment in the tumor, macrophages can either support or constrain tumor progression. It is therefore of therapeutic interest to identify the tumor-derived factors that control macrophage education. With this aim, we correlated the expression of ADAM proteases, which are key mediators of cell-cell signaling, to the expression of pro-tumorigenic macrophage markers in human cancer cohorts. We identified ADAM17, a sheddase upregulated in many cancer 2 types, as a protein of interest. Depletion of ADAM17 in cancer cell lines reduced the expression of several pro-tumorigenic markers in neighboring macrophages in vitro as well as in mouse models.Moreover, ADAM17 -/educated macrophages demonstrated a reduced ability to induce cancer cell invasion. Using mass spectrometry-based proteomics and ELISA, we identified HB-EGF and AREG, shed by ADAM17 in the cancer cells, as the implicated molecular mediators of macrophage education. Additionally, RNA-seq and ELISA experiments revealed that ADAM17-dependent HB-EGF-ligand release induces the expression and secretion of CXCL chemokines in macrophages, which in turn stimulates cancer cell invasion.In conclusion, we provide evidence that ADAM17 mediates a paracrine EGFR-ligand-chemokine feedback loop, whereby cancer cells hijack macrophages to promote tumor progression.

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

“…ADAM17-mediated JAM-A/ FIIR shedding is responsible for aging-related abnormal endothelial remodeling (156). However, other substrates, like EGFR ligands (17,97,180), E-cadherin (124), VLDLR (4), IL-11R (5), CD137 (94), P75 (11), GPIBa (6), HPP1 (119), and NRG1 (10) are precursor proteins or fusion proteins that can yield active components or soluble active receptors only after cleavage and release by ADAM17 (Figure 2). Evidence suggests that ADAM17 promotes tumor-associated macrophage polarization and angiotensin II-mediated pro-growth and promigration signals by shedding EGFR ligands, including heparinbinding EGF-like growth factor (HB-EGF) and AREG (members of the EGF family), from the cell membrane (17,32).…”

“…Our previous study showed that the expression of ADAM17 was associated with infiltration of multiple immune cells, including macrophages (20), in TCGA pan-cancer samples and yet the specific regulatory mechanism of ADAM17 is unknown. Recently, Gnosa et al have revealed the positive roles of ADAM17 in regulating the polarization of TAMs (17). By using bioinformatics analysis based on the TCGA dataset and immunohistochemical analysis from triple-negative breast cancer cohort, the authors first confirmed that highly expressed ADAM17 in tumors is positively correlated with tumorigenic macrophage markers CD163 or CD206.…”

“…More importantly, ADAM17 is contributory to the occurrence and development of cancers, including lung carcinoma (10), ovarian carcinoma (11), breast carcinoma (12)(13)(14), gastric carcinoma (15), and cervical carcinoma (16). Interestingly, it regulates some immune signaling pathways through the shedding activity, which may facilitate the inflammatory response in tumor development (17)(18)(19). However, the study of the relationship between the abnormal expression of this metalloproteinase in tumors and its immune regulation is still not well studied.…”

Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17

“…Our results suggest that it might be possible to screen for molecules that selectively affect the orientation or presentation of the cleavage site(s) of EGFR ligands and other substrate proteins to ADAM17/iR2. This could help block the activity of EGFR ligands implicated in cancer and inflammation (e.g., AREG, EREG, [ 48 , 49 , 50 , 51 , 52 ]) without affecting the function of TGFα in protection of the skin and intestinal barrier [ 13 , 16 , 17 ]. This, in turn, could provide novel treatment options for diseases that depend on the dysregulated processing of specific EGFR ligands.…”

Loss of cancer cell‐derived ADAM15 alters the tumor microenvironment in colorectal tumors

“…The protumorigenic role of ADAMs has been further confirmed in vitro and in murine cancer models, where studies have shown a role in supporting tumor growth and metastasis 15‐17 . Although the implication of ADAMs in cell‐ECM and cell‐cell interactions has been shown in vitro, 18,19 their role in the crosstalk between cancer cells and the TME in murine cancer models is scarcely explored 20‐22 …”