ERK1/2 and p38α/β signaling in tumor cell quiescence: opportunities to control dormant residual disease

Abstract

Systemic minimal residual disease after primary tumor treatment can remain asymptomatic for decades. This is thought to be due to the presence of dormant disseminated tumor cells (DTC) or micrometastases in different organs. DTCs lodged in brain, lungs, livers, and/or bone are a major clinical problem because they are the founders of metastasis, which ultimately kill cancer patients. The problem is further aggravated by our lack of understanding of DTC biology. In consequence, there are almost no rational therapies to prevent dormant DTCs from surviving and expanding. Several cancers, including melanoma as well as breast, prostate, and colorectal carcinomas, undergo dormant periods before metastatic recurrences develop. Here we review our experience in studying the cross-talk between ERK1/2 and p38α/β signaling in models of early cancer progression, dissemination, and DTC dormancy. We also provide some potential translational and clinical applications of these findings and describe how some currently used therapies might be useful to control dormant disease. Finally, we draw caution on the use of p38 inhibitors currently in clinical trials for different diseases as these may accelerate metastasis development.

Figure 1

More general schemes regarding the mechanisms of tumor cell dormancy can be found in ref. . Here we focus on data limited to the role of the ERK1/2 and p38α/β pathways. Left, signaling pathways discovered in a model of aggressive tumor cell (HEp3) reprogramming into quiescence. In vitro expansion of primary HEp3 tumor cells (proliferative tumor cells) leads to their reprogramming into a dormancy program (dormant tumor cells). A key-signaling feature of these dormant tumor cells is low ERK1/2 and high p38α activation. The resulting ERK^low/p38^high ratio induces G₀-G₁ arrest controlled by the upregulation of p53 (R213Q), NR2F1, and BHLHB3, and the downregulation of FOXM1 and c-Jun, TFs that promote G₁ exit. These signals are required for dormant HEp3 cells to enter and maintain the quiescent state. Furthermore, p38α-dependent activation of ATF6α leads to mTOR activation and subsequent basal survival of dormant HEp3 cells entering quiescence in vivo (basal survival). The ERK^low/p38^high ratio also induces expression of the chaperone BiP/Grp78, which inhibits Bax activation to prevent apoptosis. However, this survival mechanism appears to be operational only in response to added stress such as chemotherapy (adaptive survival). Integration of these 3 processes (G₀-G₁ arrest + basal survival + adaptive survival) defines the underlying mechanisms for the acquisition of a dormant phenotype. These hallmarks may be regulated by different mechanisms, depending on the context and the presence of, e.g., MSGs. In contrast, in primary proliferating tumors or tumors exiting dormancy, the ratio is reversed and the resulting ERK^low/p38^high ratio switches cell signaling to promote a proliferation phenotype. Right, potential scenarios in which dormancy (G₀-G₁ arrest + basal survival + adaptive survival) or proliferative programs might be activated. In primary expanding tumors, a proliferative scenario prevails, and tumor cells are able to disseminate carrying this cell-signaling profile. In one scenario, when these cells reach a growth-permissive target tissue microenvironment (e.g., lung), a proliferative phenotype prevails and dormancy is prevented. In contrast, in growth-restrictive sites, such as the BM, a dormant phenotype prevails (G₀-G₁ arrest + basal survival + adaptive survival). The latter scenario presupposes that DTCs are responsive to cues from the tissue microenvironment that can modulate dormancy. It is possible that perturbations of the tissue microenvironment (i.e., irradiation) or the presence of specific stromal cells such as macrophages (not depicted) that lead to tissue remodeling and cross-talk with tumor cells could interrupt dormancy, leading to metastasis.