Extracellular-Regulated Protein Kinase 5-Mediated Control of p21 Expression Promotes Macrophage Proliferation Associated with Tumor Growth and Metastasis

Russo

doi:10.1158/0008-5472.CAN-19-2416

Extracellular-Regulated Protein Kinase 5-Mediated Control of p21 Expression Promotes Macrophage Proliferation Associated with Tumor Growth and Metastasis

Russo

Authors

Dr Ilaria Russo i.russo@keele.ac.uk

Abstract

The presence of immunosuppressive macrophages that become activated in the tumor microenvironment constitutes a major factor responsible for tumor growth and malignancy. In line with this knowledge, we report here that macrophage proliferation is a significant feature of advanced stages of cancer. Moreover, we have found that a high proportion of proliferating macrophages in human tumors express ERK5. ERK5 was required for supporting the proliferation of macrophages in tumor grafts in mice. Furthermore, myeloid ERK5 deficiency negatively impacted the proliferation of both resident and infiltrated macrophages in metastatic lung nodules. ERK5 maintained the capacity of macrophages to proliferate by suppressing p21 expression to halt their differentiation program. Collectively, these data provide insight into the mechanism underpinning macrophage proliferation to support malignant tumor development, thereby strengthening the value of ERK5-targeted therapies to restore antitumor immunity through the blockade of protumorigenic macrophage activation.

Acceptance Date	Jun 12, 2020
Publication Date	Aug 15, 2020
Journal	Cancer Research
Print ISSN	0008-5472
Publisher	American Association for Cancer Research
Pages	3319 - 3330
DOI	https://doi.org/10.1158/0008-5472.CAN-19-2416
Publisher URL	https://cancerres.aacrjournals.org/content/80/16/3319