Beyond molecular tumor heterogeneity: protein synthesis takes control

Ramon y Cajal, Santiago; Castellvi, Josep; Hümmer, Stefan; Peg, Vicente; Pelletier, Jerry; Sonenberg, Nahum

Tumor cell adaptability often leads to the use of redundant signaling pathways in response to stress, such as hypoxia and reduced nutrient availability. Within a tumor bed, variations in the "strength" of these stressor events and the corresponding responses can result in a significant degree of heterogeneity in gene expression, with some cells needing to respond more acutely than others. In this review, we underscore the nature of eukaryotic initiation factor (eIF) 4E in malignant tumors as a critical effector of cell signaling networks. We summarize the findings that the phosphorylated forms of eIF4E and 4E-BP1, termed p-eIF4E and p-4E-BP1, show a predominantly homogenous expression pattern within tumor beds, a feature that we predict to be actionable and to hold significant consequences for cancer therapy. Fig. 1 a Diagram representing clonal selection according to a Darwinian model. The best-adapted clones due to genetic or epigenetic advantages or with better interplay with neighboring cells will survive and proliferate, becoming the dominant clone until a new "selective barrier" appears. The tumor clonal composition varies over time, although, microscopically, these changes can be subtle or not evident. b Clonal cooperation and feature complementation. Puzzle diagram illustrating the contribution of individual cell clones with different tumor-promoting features to the formation of a tumor. The main feature of each clonal population within a tumor is shown as legend on the left side. The cooperation between different clones results in different functional consequences for the tumor, which are summarized in the middle of the figure Clonal evolution during cancer progression A complex molecular scenario is responsible for tumor initiation and tumor progression. It is well established that, in a single tumor, cell clones with novel genetic alterations arise constantly and are selected according to a Darwinian model [3] . Concomitantly, there is also cross talk between the tumor clones and the microenvironment that affect the ability of tumors to survive and proliferate. In fact, the cooperation between clones and the microenvironment is similar to that of a tumor consortium (Fig. 1 ) [4] . The new genetic alterations are driven by genetic instability, one of the hallmarks of tumor cells [5] . Only a small proportion of the total mutational burden is related to the process of clonal evolution because most are passenger mutations with no biological relevance [5] . In addition, treatments can alter clonal heterogeneity by selecting for more resistant cells or perturbing the microenvironmental conditions [6] .