Cancer Plasticity: The Role of mRNA Translation

Abstract

Tumor progression is associated with dedifferentiated histopathologies concomitant with cancer cell survival within a changing, and often hostile, tumor microenvironment. These processes are enabled by cellular plasticity, whereby intracellular cues and extracellular signals are integrated to enable rapid shifts in cancer cell phenotypes. Cancer cell plasticity, at least in part, fuels tumor heterogeneity and facilitates metastasis and drug resistance. Protein synthesis is frequently dysregulated in cancer, and emerging data suggest that translational reprograming collaborates with epigenetic and metabolic programs to effectuate phenotypic plasticity of neoplasia. Herein, we discuss the potential role of mRNA translation in cancer cell plasticity, highlight emerging histopathological correlates, and deliberate on how this is related to efforts to improve understanding of the complex tumor ecology.

Keywords: cancer plasticity; mRNA translation; metabolism; protein synthesis; stromal–epithelial interactions; therapy resistance; tumor microenvironment.

Figure 1.. Cancer Progression and Plasticity.

Cancer progression is characterized by increasing cell plasticity. Neoplastic growth is also frequently accompanied by limitations in energy supply due to hypoxia or low nutrient availability. This, in turn, limits eIF4F complex assembly and TC recycling, which are both essential for efficient global translation. Thus, translational reprogramming under limited oxygen and nutrient supply in the TME is characterized by a reduction in global protein synthesis and increased selective translation of mRNAs essential for adaptation and survival, including NODAL, SNAI1, and ATF4. Red arrow indicates a decrease. Green arrow indicates an increase. Abbreviations: ATF4, activating transcription factor 4; eIF, eukaryotic translation initiation factor; GTP, guanosine triphosphate; m⁷G, 7-methylguanosine; Met, methionine; TC, ternary complex; TME, tumor microenvironment.

Figure 2.. Regulation of Translation Initiation via Mechanistic/Mammalian Target of Rapamycin (mTOR) and the Integrated Stress Response (ISR).

Various stressors act via the mTOR (left) and/or the ISR network (right) that in turn impinge on the translational machinery. mTOR inhibition prevents the phosphorylation of 4E-BPs, which prevents eIF4E:eIF4G binding and interferes with eIF4F complex formation. Protein synthesis is further modulated by the phosphorylation of eIF4E via MNK1/2, although this process is incompletely understood. mTOR inhibition also leads to an activation of eEF2K, resulting in phosphorylation of eEF2 and a reduction in translation elongation (dashed lines denote indirect effects). Induction of ISR is mediated by four different kinases that phosphorylate eIF2α in response to different types of stress. Phosphorylation of eIF2α attenuates GEF activity of eIF2B, thereby decreasing ternary complex (TC; i.e., eIF2: $\text{tRNA}{}_{\text{i}}^{\text{Met}:}\text{GTP}$) levels. However, under these conditions of reduced global translation, select subsets of mRNAs encoding crucial stress response factors, such as ATF4, are translationally upregulated. Elevated eIF4F and TC levels allow high translation rates when energy and oxygen supply are not limiting. Conversely, conditions wherein the levels of eIF4F and TC are low denote translationally repressive states induced by various stressors, resulting in a global reduction in translation. Abbreviations: 4E-BP, 4E-binding proteins; ATF4, activating transcription factor 4; dsRNA, double-stranded RNA; eEF2K, eukaryotic translation elongation factor 2 kinase; eIF, eukaryotic translation initiation factor; ERK, extracellular signal-regulated kinase; GCN2, general control nonderepressible; GDP, guanosine diphosphate; GTP, guanosine triphosphate; HRI, heme-regulated inhibitor; MAPK, mitogen-activated protein kinase; Met, methionine; MNK, MAPK-interacting kinase; mTOR, mammalian/mechanistic target of rapamycin; P, protein phopsphorylation; PERK, PKR-like endoplasmic reticulum kinase; PKR, RNA-activated protein kinase.

Figure 3.. Extrinsic Cues Drive Plasticity through Translational Mechanisms.

Extrinsic cues that drive plastic phenotypes in cancer converge on the mechanistic/mammalian target of rapamycin complex 1 and the integrated stress response, ultimately leading to translational reprogramming. Cellular plasticity is underscored by adaptive processes, and the translational responses to stressors are highly context dependent. Dashed lines indicate new discoveries in the field that, as of yet, have not been robustly verified. Abbreviations: eEF2K, eukaryotic translation elongation factor 2 kinase; eIF, eukaryotic translation initiation factor; ERK, extracellular signal-regulated kinase; GTP, guanosine triphosphate; ISRIB, integrated stress response inhibitor; m⁷G, 7-methylguanosine; MAPK, mitogen-activated protein kinase; Met, methionine; MNK1/2, MAPK-interacting kinases 1/2; mTORC1, mechanistic/mammalian target of rapamycin complex 1; TGFβ, transforming growth factor β.