# Hippo Pathway Dysregulation in Thymic Epithelial Tumors (TETs): Associations with Clinicopathological Features and Patients’ Prognosis

## TL;DR

This study explores how the Hippo pathway is disrupted in thymic tumors and how these disruptions relate to tumor behavior and patient outcomes.

## Contribution

The first comprehensive analysis of Hippo pathway components in thymic epithelial tumors and their associations with clinicopathological features and prognosis.

## Key findings

- Cytoplasmic TEAD4 overexpression is linked to poorer survival in thymic epithelial tumors.
- Early-stage tumors show higher nuclear YAP1 and AYAP, while advanced-stage tumors exhibit cytoplasmic MST1, LATS1, and MOB1A.
- Altered Hippo pathway compartmentalization correlates with tumor aggressiveness and clinical stage.

## Abstract

Thymic epithelial tumors (TETs) display heterogeneous histology and often unpredictable clinical behavior. The Hippo signaling pathway has been implicated in tumorigenesis, but its role in TETs remains poorly characterized. We performed the first comprehensive immunohistochemical analysis of core and upstream Hippo pathway components—YAP1, active YAP (AYAP), TAZ, LATS1, MOB1A, MST1, SAV1, and TEAD4—in 77 TETs. Associations with clinicopathological parameters and survival were explored. We observed widespread expression of Hippo components in TETs with significant associations among molecules and differences in subcellular localization and expression in normal tissue. Early stage TETs showed higher nuclear YAP1 (p = 0.032) and AYAP (p = 0.007), while cytoplasmic MST1 (p = 0.002), LATS1 (p = 0.007), MOB1A (p = 0.033) and TEAD4 (p < 0.001) correlated with advanced stage. Cytoplasmic MST1 (p = 0.014), LATS1 (p < 0.001) and TEAD4 (p = 0.005) were associated with histological aggressiveness. Cytoplasmic TEAD4 overexpression was associated with poorer overall survival (log-rank, <70% versus ≥70%, p = 0.003). Our findings provide novel insights into the differential regulation and compartmentalization of Hippo components in TETs. While indolent tumors show features that are consistent with partial Hippo inactivation, more aggressive phenotypes exhibit reduced nuclear YAP/TAZ and altered TEAD4 compartmentalization, suggesting a context-dependent Hippo signaling state. Cytoplasmic TEAD4 emerges as a potential adverse prognosticator, indicating involvement in non-canonical or Hippo-independent mechanisms.