Beyond molecular tumor heterogeneity: protein synthesis takes control

Abstract

One of the daunting challenges facing modern medicine lies in the understanding and treatment of tumor heterogeneity. Most tumors show intra-tumor heterogeneity at both genomic and proteomic levels, with marked impacts on the responses of therapeutic targets. Therapeutic target-related gene expression pathways are affected by hypoxia and cellular stress. However, the finding that targets such as eukaryotic initiation factor (eIF) 4E (and its phosphorylated form, p-eIF4E) are generally homogenously expressed throughout tumors, regardless of the presence of hypoxia or other cellular stress conditions, opens the exciting possibility that malignancies could be treated with therapies that combine targeting of eIF4E phosphorylation with immune checkpoint inhibitors or chemotherapy.

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

Fig. 2

Schematic representing the signaling cascade regulating translation initiation. The key event is the dissociation of eIF4E from 4E-BP1 by different signaling pathways under normal growth conditions and in response to stress

Fig. 3

a–h Invasive ductal carcinoma a–g (×200), h (×400). Immunohistochemistry for a p-ERK1/2, b p-S6, c p-4E-BP1, d p-eIF4E, e p-AKT, and f p-mTOR. g, h GLUT-1 Immunohistochemistry was performed as described previously [58] using the following primary antibodies: p-eIF4E (Abcam, Ab76256), p-4E-BP1 (T37/46) (Cell Signaling, #2855), pS6 (S235/236) (Cell Signaling, #2211), p-ERK1/2 (T202/Y204) (Cell Signaling, #9101), p-mTOR (Ser2448) (Cell Signaling #2971); p-Akt (Ser473) (Cell Signaling #3787), GLUT-1 (Abcam, Ab652)

Fig. 4

a–d Low-grade lung adenocarcinoma (×400). e–h High-grade lung squamous carcinoma (×200). Immunohistochemistry for p-ERK1/2 (a, e), p-S6 (b, f), p-4E-BP1 (c, g), and p-eIF4E (d, h). Immunohistochemistry was performed as described previously [58]

Fig. 5

a Schematic drawing of a tumor and the tumor microenvironment. Left: Cells within a tumor exposed to different microenvironmental cues. Nutrient and O₂ supply decreases from the periphery to the center of the tumor while stress conditions are elevated. Right: Genetic alterations of cells within a tumor are depicted by different colors. Importantly, genetic alterations are not strictly limited to the different environmental conditions. b Scheme depicting the staining pattern of different proteins involved in the signaling cascade regulating translation initiation (top), as shown in Figs. 3 and 4. GLUT1 serves as a marker for hypoxic conditions within the tumor (bottom)