Hippo-YAP/TAZ Signaling in Hematological Malignancies: Molecular Mechanisms, Pathway Crosstalk and Therapeutic Potential

The Multifaceted Roles of the Hippo-Yes-Associated Protein (YAP)/Transcriptional Coactivator with a PDZ-Binding Motif Pathway in Regulating the Tumor Microenvironment.

This work discusses recent advances in understanding how this pathway modulates the immune landscape, cancer-associated fibroblasts, and tumor vasculature and outlines how YAP/TAZ drives fibroblast activation, matrix stiffening, and promotes cancer-associated fibrosis.

Crosstalk between the Wnt pathway and other signaling pathways.

The Wnt/β-catenin signaling pathway is a deeply conserved regulatory network that governs embryonic development, stem cell maintenance, and tissue homeostasis. Aberrant activation of the Wingless/Integrated protein (Wnt) signaling is a hallmark of numerous human diseases, most prominently in colorectal cancer, where it cooperates with additional oncogenic pathways to drive tumor initiation, progression, and therapeutic resistance (See Supplementary Table 1 for a list of the abbreviations used in this manuscript and their definitions.). Increasing evidence indicates that Wnt signaling does not function as an isolated linear cascade but rather as an integrative signaling hub that dynamically interfaces with major signaling pathways, including the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways. Rat Sarcoma protein (RAS)- Rapidly Accelerated Fibrosarcoma protein (RAF)- Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)- Ak strain transforming protein (AKT)- Mechanistic Target of Rapamycin (mTOR) pathways. These interactions occur at multiple molecular levels, encompassing shared kinases, transcriptional regulators, metabolic nodes, and cytoskeletal components, thereby coordinating proliferative, metabolic, and migratory programs. In this review, we synthesize current mechanistic and clinical insights into the crosstalk between Wnt signaling and the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways, with particular emphasis on colorectal cancer. We discuss how these signaling networks converge to regulate β-catenin stability, transcriptional activity, cell adhesion, and metabolic reprogramming, thereby generating oncogenic phenotypes that cannot be explained by activation of individual pathways alone. To illustrate the evolutionary conservation and biological significance of these interactions, we integrate developmental paradigms from early Xenopus embryogenesis, where Wnt signaling governs zygotic genome activation, body axis formation, and the regulation of cell growth, protein stability, and biomass accumulation. Finally, we examine how an improved understanding of Wnt-centered signaling networks is informing emerging therapeutic strategies, including combinatorial pathway inhibition and nanoparticle-based drug delivery. Collectively, this review highlights Wnt signaling as a central integrator of developmental and oncogenic programs, providing a conceptual framework for understanding signaling network crosstalk and identifying new therapeutic opportunities in cancer.

The Crosstalk Between YAP/TAZ and Cancer Metabolism: From Mechanistic Insights to Drug Discovery

As the core transcriptional co-activators of the Hippo signaling pathway, YAP and TAZ play essential roles in maintaining tissue homeostasis and in tumorigenesis. Their aberrant activation is frequently observed in human malignancies, and accumulating evidence has identified them as crucial drivers of tumor initiation and progression. YAP/TAZ have been recently recognized as key regulators of cellular metabolic reprogramming, a hallmark of cancer that fuels tumor cell proliferation by rewiring glucose, lipid, amino acid, and nucleotide metabolism. Conversely, the activity of YAP/TAZ is modulated by metabolites such as glucose and lipids, establishing a complex bidirectional regulatory circuit. Therefore, deciphering this intricate crosstalk is of great importance for cancer therapy and drug discovery. In this review, we systematically clarify the interplay between YAP/TAZ and metabolic reprogramming in cancer, delineate the core molecular networks through which YAP/TAZ govern each metabolic pathway, and summarize the current pharmacological inhibitors targeting YAP/TAZ-regulated metabolic networks. Collectively, these findings pave the way for therapeutic approaches targeting YAP/TAZ-driven metabolic vulnerabilities in cancer.

The multifaceted role of SOCS3 in colorectal cancer: molecular mechanisms and clinical implications

Hippo-YAP1 dysregulation as a central driver of therapeutic resistance in cancer: mechanisms and targeting therapeutic strategies.

A review summarizes the close link between Hippo-YAP1 dysregulation and drug resistance, and highlights intervention strategies with the potential to serve as novel treatment strategies.

Targeting Yes-Associated Protein (YAP)/Transcriptional Coactivators with PDZ-Binding Motif (TAZ)-Transcriptional Enhanced Associate Domain (TEAD) for Cancer and Regenerative Medicine.

The evolutionarily conserved Hippo signaling pathway is crucial for regulating organ size, tissue homeostasis, and regeneration. Mammalian Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and its interaction with transcriptional enhanced associate domain 1-4 (TEAD1-4) are vital for transcriptional outputs linked to cell proliferation and apoptosis. Dysregulation of Hippo signaling is associated with various aspects of cancer biology. The convergence of the Hippo signaling network with diverse oncogenic pathways places it at the center of tumorigenic adaptation, maintenance of stemness, and the development of drug resistance. Modulating YAP/TAZ-TEAD signaling offers broad therapeutic potential, from cancer treatment to regenerative medicine. Several small-molecule TEAD inhibitors are at various stages of clinical development, with increasing efforts focused on monotherapy and combination therapies targeting YAP/TAZ hyperactivation caused by standard-of-care (SOC) drugs (best available disease-specific treatments used in clinics), particularly targeted therapies.