Jun 2026· Cold Spring Harbor Perspectives in Biology· pp. a041912· 0 citations
Medicine
TL;DR
This review synthesizes current evidence on the roles and regulation of the Hippo pathway in neural progenitor cells, glial cells, and neurons, highlighting context-dependent mechanisms and outstanding questions and uncovers new strategies for tumor therapy and neural repair.
Abstract
The Hippo pathway prevents tissue overgrowth and tumorigenesis in many organs across species. Not surprisingly, this pathway limits the proliferation of progenitor cells in diverse regions of the nervous system, and its dysregulation can lead to neural tumors in humans. However, the functions of the Hippo pathway extend beyond proliferation control. Recent studies have revealed a remarkable functional diversity across neural lineages, encompassing morphogenesis, cell fate, tissue maintenance, and repair. This review synthesizes current evidence on the roles and regulation of the Hippo pathway in neural progenitor cells, glial cells, and neurons, highlighting context-dependent mechanisms and outstanding questions. With the core molecular machinery and many fundamental cellular functions of the Hippo pathway now established, the field is entering a new phase: unraveling the functional significance and regulatory complexity of Hippo signaling in physiologically relevant contexts-both normal and diseased-promises to deepen our mechanistic understanding of neural development and homeostasis, and unlock new strategies for tumor therapy and neural repair.
The Hippo pathway is an evolutionarily conserved regulator of growth, regeneration, and organ homeostasis, and while its dysregulation is well established in cancer, the effects of inhibiting this pathway on normal tissues are less understood. Here we have systematically investigated the impact of Hippo pathway inhibition by comparing pharmacologic perturbation using a covalent small-molecule TEAD inhibitor (TEADi CMPD1, also known as GNE-8025) with genetic suppression of YAP/TAZ. We identified three key target organs that consistently emerged upon TEAD inhibition: the kidney, as well as the pancreas, and thymus. Across models, both perturbations led to comparable disease phenotypes in these organs, including tubular degeneration in the kidney, acinar atrophy in the pancreas, and lymphoid depletion in the thymus. However, the extent of damage was more pronounced in mice treated with the small-molecule inhibitor, highlighting potential dose and compound specific effects while remaining broadly consistent with the phenotypes observed upon genetic ablation of YAP/TAZ. This highlights the key role of evaluating both genetic and pharmacological perturbations to characterize the phenotypes and potential toxicities when modulating novel targets in oncology. To further investigate the mechanisms underlying pan-TEAD inhibition and kidney related adverse effects, we further characterized this class effect through a comprehensive transcriptomic analysis of the kidney to map the pathways involved in renal response. Significance Understanding on target toxicities is critical for the safe clinical development of TEAD inhibitors. Here, by integrating pharmacologic TEAD inhibition with genetic suppression by developing a mouse model that characterizes systemic, inducible knockdown of YAP/TAZ, we provide a systematic framework to define the Hippo pathway liabilities in vivo. We identify kidney, pancreas, and thymus as conserved target organs with concomitant phenotypes across both genetic and pharmacological methods, establishing these as pathway driven effects. Importantly, we uncover dose dependent and partially irreversible injury, particularly in kidney and pancreas, alongside mechanistic insight linking TEAD inhibition to aldosterone signaling disruption in kidney. These findings highlight the importance of strategies to identify monitorable, manageable adverse effect to guide clinical translation of TEAD targeting strategies.
Sayantanee Paul, Michelle Lepherd, Thijs J. Hagenbeek et al.· bioRxiv· 0 citations
This review summarizes the core components and regulatory mechanisms of the Hippo pathway, describes its role in cardiac development, and elucidates the molecular mechanisms by which it contributes to ventricular septal defect, tetralogy of Fallot, and left ventricular noncompaction cardiomyopathy, aiming to provide a new theoretical basis for the early diagnosis and treatment of CHD.
Qingxiu Li, Jiayi Chen, Yibing Zhu et al.· Zhongguo dang dai er ke za z...· 0 citations
The deltex (DTX) gene family encodes RING-type E3 ubiquitin ligases that are central to the regulation of the Notch signaling pathway, a mechanism governing cell fate, differentiation, proliferation, and apoptosis during development and adult tissue homeostasis. In Drosophila melanogaster, the Deltex (Dx) fine-tunes Notch signaling by modulating receptor endocytosis and degradation, acting as either an enhancer or a suppressor depending on the context. Insights from flies have revealed the evolutionary conservation of the Dx-Notch interaction across species, including humans. However, recent studies have expanded this view, identifying Dx as a regulator of multiple signaling pathways beyond Notch, specifically Wingless, Decapentaplegic, and Toll, underscoring its role as a hub for cellular communication. Through its broad regulatory network, Dx influences fundamental processes including cell growth, differentiation, apoptosis, and homeostasis. Dysregulation of Dx expression and function has been implicated in several diseases, ranging from cancer to immunological disorders and congenital abnormalities, positioning it as a promising therapeutic target. Despite these advances, important gaps remain in our understanding of Dx substrates, molecular mechanisms, and their full spectrum of physiological and pathological roles. Future research will be crucial to uncovering the broader biology of DTX family proteins and enabling their clinical application as diagnostic and prognostic markers. This review consolidates current knowledge and emerging insights on Dx, providing a framework to guide future research and therapeutic exploration.
Vartika Sharma, Pratikshya Sahoo, M. Mutsuddi et al.· Cellular and Molecular Life...· 0 citations
This review provides a comprehensive and integrative analysis of NEDD9 by systematically linking its structural features, multilayered regulatory mechanisms, diverse biological functions, and clinical relevance within a unified conceptual framework.
Yu Zhang, Lin Li, Ya Zhang et al.· Pathology, Research and Prac...· 0 citations
The nervous system has emerged as a critical regulator of cancer progression. Recent studies demonstrate that peripheral neurons shape tumor growth, dissemination, and therapeutic response by regulating multiple components of the tumor microenvironment. In parallel, tumors within the body remodel their neural niche by recruiting innervation and modulating neuronal phenotype and activity. This bidirectional cross talk positions neural circuits as integral components of the tumor ecosystem, linking environmental cues, including metabolic stress, inflammation, and the impact of treatment, to coordinated multicellular responses that promote progression and treatment resistance. Here, we review the field of cancer neuroscience with a focus on solid tumors originating outside the central nervous system. We synthesize mechanistic insights into how the peripheral nervous system shapes the tumor microenvironment to influence tumor behavior and highlight emerging therapeutic opportunities to target neural pathways. Together, these findings identify the nervous system as an upstream regulator of cancer biology and a tractable target for intervention.
Aeson Chang, Shenghong Zhu, Terrance Lam et al.· Journal of Experimental Medi...· 0 citations
Dysregulation of intracellular signaling networks underpins cancer. Yet, resolving signaling networks within distinct or rare cell types in cancer in vivo has been unattainable. Here we develop INSIGHT by integrating cell sorting with mass spectrometry to enable quantitative phosphoproteomics and proteomics of discrete cell types from fixed tissues. Using INSIGHT, we map the signaling network within disseminating glioblastoma cells from patient-derived xenografts implanted in mice. Disseminating tumor cells undergo a proteome-wide shift from proliferative to mesenchymal, neural progenitor-like cell states. In parallel, signaling network and global kinase activity are rewired, transitioning from cell cycle-associated circuitries to those governing synaptic function, neuronal migration, and ion channel activity. Changes begin at the tumor margin and persist in distant brain parenchyma. Hornerin and phosphorylation of Ca²⁺-permeable GluA2 at Y876 were identified as mediators of glioblastoma progression. INSIGHT enables systems-level dissection of cell-type-specific signaling circuitries in vivo across wide range of biological systems.
Ryuhjin Ahn, Alicia D’Souza, L. Long et al.· Nature Communications· 0 citations