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

• Published in: International journal of cancer 2023-12, Vol.153 (12), p.2068-2081
• Main Authors: Puig‐Blasco, Laia, Piotrowski, Krzysztof B., Michaelsen, Signe R., Bager, Nicolai S., Areškevičiūtė, Aušrinė, Thorseth, Marie‐Louise, Sun, Xiao‐Feng, Keller, Ulrich auf dem, Kristensen, Bjarne W., Madsen, Daniel H., Gnosa, Sebastian P., Kveiborg, Marie
• Format: Article
• Language: English
• Subjects: Animal models; Antigen-presenting cells; Apoptosis; Cancer; Colon cancer; Colorectal cancer; CYR61 protein; Dendritic cells; Extracellular matrix; Immunotherapy; Infiltration; Leukocyte migration; Leukocytes (granulocytic); Lymphocytes T; Macrophages; Medical research; Metastases; Tumor microenvironment; Tumors; Up-regulation
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.34695

Tumor progression and response to treatment are highly affected by interactions between cancer cells and the tumor microenvironment (TME). Many of the soluble factors and signaling receptors involved in this crosstalk are shed by a disintegrin and metalloproteinases (ADAMs). Upregulation of ADAM15 has been linked to worse survival in cancer patients and a tumor‐promoting function both in vitro and in murine cancer models. Although ADAM15 has been involved in cell‐cell and cell‐extracellular matrix interactions, its role in the crosstalk between cancer cells and the TME in vivo remains unexplored. Therefore, we aimed to understand how ADAM15 regulates the cell composition of the TME and how it affects tumor progression. Here, we showed an upregulation of ADAM15 in tumor tissues from rectal cancer patients. Subcutaneous injection of wildtype and ADAM15‐knockout CT26 colon cancer cells in syngeneic mice confirmed the protumorigenic role of ADAM15. Profiling of tumors revealed higher immune cell infiltration and cancer cell apoptosis in the ADAM15‐deficient tumors. Specifically, loss of ADAM15 led to a reduced number of granulocytes and higher infiltration of antigen‐presenting cells, including dendritic cells and macrophages, as well as more T cells. Using in vitro assays, we confirmed the regulatory effect of ADAM15 on macrophage migration and identified ADAM15‐derived CYR61 as a potential molecular mediator of this effect. Based on these findings, we speculate that targeting ADAM15 could increase the infiltration of immune cells in colorectal tumors, which is a prerequisite for effective immunotherapy.