Expected and unexpected effects after systemic inhibition of Hippo transcriptional output in cancer

Abstract

Hyperactivation of YAP/TAZ, the Hippo pathway downstream effectors, is common in human cancer. The requirement of YAP/TAZ for cancer cell survival in preclinical models, prompted the development of pharmacological inhibitors that suppress their transcriptional activity. However, systemic YAP/TAZ inhibition may sometimes have unpredictable patient outcomes, with limited or even adverse effects because YAP/TAZ action is not simply tumor promoting but also tumor suppressive in some cell types. Here, we review the role of the Hippo pathway in distinct tumor cell populations, discuss the impact of inhibiting Hippo output on tumor growth, and examine current developments in YAP/TAZ inhibitors.

Fig. 1. Tumor promoting functions of YAP/TAZ in cancer cells.

A YAP and TAZ are frequently activated in cancer cells, where they exert tumor promoting functions. In most types of cancer cells, their activation promotes cancer progression by stimulating cell proliferation, survival, and migration. B YAP/TAZ activation in cancer cells can also promote tumor growth by non-cell autonomously modulating the activity of tumor associated cells. YAP and TAZ in cancer cell can indirectly suppress the differentiation and activation of cytotoxic T-cells cells and the recruitment and differentiation immune suppressive cells such as Treg and tumor-associated M2-like macrophages by regulating the expression of immune modulatory signaling proteins. Also, YAP and TAZ activation in cancer cells promotes the expression of pro-angiogenic factors, such as VEGF, leading to the formation of new blood vessels that supply nutrients and oxygen to the growing tumor. Thus, tumor growth is orchestrated by cell autonomous and non-cell autonomous effects of YAP/TAZ in cancer cells. PD1, Programmed Cell Death 1; PD-L1, Programmed Cell Death 1 Ligand 1.

Fig. 2. Tumor promoting functions of YAP/TAZ activity in tumor-associated cells.

A YAP and TAZ can induce tumor growth by promoting the recruitment and differentiation of immune suppressive cells such as tumor-associated M2-like macrophages and Tregs or by inhibiting the differentiation and activation of cytotoxic T-cells. B YAP and TAZ activation in endothelial cells stimulates their migration and proliferation, which is required for tumor angiogenesis. Therefore, inhibiting YAP and TAZ in endothelial cells could potentially decrease tumor growth by reducing tumor angiogenesis, which would deplete the supply of nutrients and oxygen to the tumor. Treg, regulatory T-cell.

Fig. 3. Tumor suppressive functions of YAP/TAZ in cancer cells.

A YAP/TAZ activation in cancer cells can also cell autonomously trigger tumor suppression. This is because in some types of cancers, such as breast, colon and hematological cancers, YAP/TAZ activation induces cancer cell death. B YAP/TAZ activation in cancer cells can inhibit tumor growth by non-cell autonomously activating tumor suppressive T-cells. This is because YAP/TAZ activation in cancer cells promotes the production and secretion of exosomes that stimulate antigen presenting cells and activate T-cells in the tumor microenvironment.

Fig. 4. Anti-tumor functions of YAP/TAZ in non-cancer cells.

A TAZ activation in naïve T-cells potentiates the differentiation and function of effector T-cells, leading to cancer cell elimination. B YAP and TAZ elevate the fitness of cells in cell competition, a process by which cells within a tissue compete for survival and growth. Higher levels of YAP/TAZ activation confer a selective advantage to cells (“winner” cells), promoting their growth and proliferation, which can contribute to tumorigenesis, while lower levels of YAP/TAZ activation reduce the competitive potential of cells and turn them into “loser” cells. Depending on the levels of YAP/TAZ activation, both tumor cells or normal surrounding cells can acquire either winner or loser phenotypes. Therefore, the tumor promoting and the tumor suppressing functions of YAP/TAZ in cell competition thus depend on the specific context and the cellular compartment in which they are activated.

Fig. 5. Small molecule YAP/TAZ-TEAD inhibitors.

Several approaches and inhibitors have been developed to target YAP/TAZ, their interaction with TEAD transcription factors, and the transcriptional output of the Hippo pathway. This figure lists some of the inhibitors used to inhibit YAP/TAZ-TEAD transcriptional activity and their mode of action, which include promoting degradation of mRNA encoding for YAP, inducing YAP/TAZ protein degradation, interfering with the binding of YAP/TAZ to TEAD transcription factors and blocking YAP/TAZ nuclear localization.