{"id":596,"date":"2025-07-21T02:20:08","date_gmt":"2025-07-21T02:20:08","guid":{"rendered":"https:\/\/oralpathology.hiroshima-u.ac.jp\/?page_id=596"},"modified":"2025-07-29T15:35:18","modified_gmt":"2025-07-29T15:35:18","slug":"research-en","status":"publish","type":"page","link":"https:\/\/oralpathology.hiroshima-u.ac.jp\/index.php\/research-en\/","title":{"rendered":"Research"},"content":{"rendered":"\t\t<div data-elementor-type=\"wp-page\" data-elementor-id=\"596\" class=\"elementor elementor-596\">\n\t\t\t\t<div class=\"elementor-element elementor-element-d966f32 e-flex e-con-boxed e-con e-parent\" data-id=\"d966f32\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-aaaf460 elementor-widget elementor-widget-heading\" data-id=\"aaaf460\" data-element_type=\"widget\" data-widget_type=\"heading.default\">\n\t\t\t\t\t<h1 class=\"elementor-heading-title elementor-size-default\">Research Overview<\/h1>\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-bea5685 e-flex e-con-boxed e-con e-parent\" data-id=\"bea5685\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-09878a5 elementor-widget elementor-widget-text-editor\" data-id=\"09878a5\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t\t\t\t\t\t<div class=\"video-hero-wrapper\">\n  <video id=\"bg-video\" autoplay muted loop playsinline>\n    <source src=\"https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/iStock-2202842849.mp4\" type=\"video\/mp4\" \/>\n    \u304a\u4f7f\u3044\u306e\u30d6\u30e9\u30a6\u30b6\u3067\u306f\u52d5\u753b\u304c\u518d\u751f\u3067\u304d\u307e\u305b\u3093\u3002\n  <\/video>\n  <div class=\"video-text-overlay\">\n    <h2>Genetic alterations and cell signaling research<\/h2>\n  <\/div>\n<\/div>\n\n<style>\nbody, html {\n  margin: 0;\n  padding: 0;\n}\n\n.video-hero-wrapper {\n  position: relative;\n  width: 100vw;\n  height: 600px;\n  overflow: hidden;\n  z-index: 1;\n  margin-left: calc(-50vw + 50%);\n}\n\n#bg-video {\n  position: absolute;\n  top: 50%;\n  left: 50%;\n  transform: translate(-50%, -50%);\n  min-width: 100%;\n  min-height: 100%;\n  object-fit: cover;\n  z-index: -1;\n  background: black;\n}\n\n.video-text-overlay {\n  position: absolute;\n  bottom: 30px;\n  left: 30px;\n  color: white;\n  font-size: 1.8rem;\n  text-align: left;\n  z-index: 2;\n  text-shadow: 0 0 10px rgba(0,0,0,0.7);\n}\n<\/style>\n\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-8baac3f e-flex e-con-boxed e-con e-parent\" data-id=\"8baac3f\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-17619c6 elementor-widget elementor-widget-heading\" data-id=\"17619c6\" data-element_type=\"widget\" data-widget_type=\"heading.default\">\n\t\t\t\t\t<h2 class=\"elementor-heading-title elementor-size-default\">Understanding Cancer<br>\n\u2014 Why Genetic Alterations and Signaling Pathways Matter \u2014<\/h2>\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-cee479f e-flex e-con-boxed e-con e-parent\" data-id=\"cee479f\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-6f9aada elementor-widget elementor-widget-text-editor\" data-id=\"6f9aada\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t\t\t\t\t\t<p data-start=\"118\" data-end=\"576\">Inside cells, numerous signaling pathways operate in concert. In healthy cells, receptors on the cell surface receive survival signals\u2014such as ligands\u2014from the extracellular environment. This activates intracellular molecules through phosphorylation, which in turn phosphorylate and activate downstream targets. These sequential events ultimately promote the transcription of genes required for cell proliferation and survival, thereby enhancing cell growth.<\/p><p data-start=\"578\" data-end=\"1074\">In cancer, however, various signaling pathways are either abnormally activated or inactivated, leading to uncontrolled cell proliferation. At the root of these disruptions are <strong data-start=\"754\" data-end=\"777\">genetic alterations<\/strong>. Mutations, gene amplifications, deletions, and gene fusions can activate <strong data-start=\"852\" data-end=\"865\">oncogenes<\/strong>\u2014genes that promote cell growth\u2014or inactivate <strong data-start=\"911\" data-end=\"937\">tumor suppressor genes<\/strong>, which normally function to prevent excessive proliferation. As a result, signaling cascades downstream of these genes are dysregulated.<\/p><p data-start=\"1076\" data-end=\"1533\">Among these alterations, some have little biological consequence (known as <strong data-start=\"1151\" data-end=\"1174\">passenger mutations<\/strong>), while others play a critical role in tumor growth (known as <strong data-start=\"1237\" data-end=\"1257\">driver mutations<\/strong>). The concept behind <strong data-start=\"1279\" data-end=\"1309\">molecular targeted therapy<\/strong> is to inhibit these driver mutations or their downstream signaling pathways, ideally damaging cancer cells while sparing normal ones. Today, molecular targeted drugs have become an essential component of cancer treatment.<\/p><p data-start=\"1535\" data-end=\"2119\">For example, <strong data-start=\"1548\" data-end=\"1580\">immune checkpoint inhibitors<\/strong>, a type of targeted therapy, have emerged in recent years. These agents block mechanisms by which cancer cells suppress immune responses. One such mechanism involves <strong data-start=\"1747\" data-end=\"1756\">PD-L1<\/strong> on cancer cells binding to <strong data-start=\"1784\" data-end=\"1792\">PD-1<\/strong> on T cells, thereby inactivating them. Antibodies like <strong data-start=\"1848\" data-end=\"1861\">Nivolumab<\/strong> and <strong data-start=\"1866\" data-end=\"1883\">Pembrolizumab<\/strong> block this interaction, reactivating T cells to attack tumors. In oral and head and neck squamous cell carcinoma, <strong data-start=\"1998\" data-end=\"2011\">Cetuximab<\/strong>, an anti-EGFR antibody, is approved for use, targeting the often amplified and overexpressed <strong data-start=\"2105\" data-end=\"2113\">EGFR<\/strong> gene.<\/p><p data-start=\"2121\" data-end=\"2664\">In 2019, Japan launched a nationwide <strong data-start=\"2158\" data-end=\"2184\">cancer genome medicine<\/strong> initiative. Using next-generation sequencing (NGS), clinicians can identify genetic alterations in a patient\u2019s tumor and choose targeted therapies that inhibit driver mutations or downstream signaling pathways. Traditionally, drug approval was organ-specific\u2014limited to the tissue where the cancer originated\u2014but genome medicine is changing this paradigm. By focusing on the genetic profile rather than the tumor\u2019s anatomical site, we are moving closer to <strong data-start=\"2641\" data-end=\"2663\">precision medicine<\/strong>.<\/p><p data-start=\"2666\" data-end=\"2906\">However, a significant challenge remains: even when a genetic alteration is identified, if the downstream signaling pathways are poorly understood or no targeted therapies exist, we cannot translate these findings into effective treatments.<\/p><p data-start=\"2908\" data-end=\"3234\">This is why it is critically important to investigate <strong data-start=\"2962\" data-end=\"3025\">which genetic alterations regulate which signaling pathways<\/strong>. Clarifying this relationship will not only enhance our understanding of cancer biology but also accelerate the development of future targeted therapies\u2014bringing us closer to improved treatments for patients.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-d3b7f4e e-flex e-con-boxed e-con e-parent\" data-id=\"d3b7f4e\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-ea3904a elementor-widget elementor-widget-heading\" data-id=\"ea3904a\" data-element_type=\"widget\" data-widget_type=\"heading.default\">\n\t\t\t\t\t<h2 class=\"elementor-heading-title elementor-size-default\">A Critical Signaling Pathway in Cancer Cells<br>\n\u2014 The Hippo Pathway and YAP\/TAZ \u2014<\/h2>\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-48c912e e-flex e-con-boxed e-con e-parent\" data-id=\"48c912e\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-adfa2c0 elementor-widget__width-inherit elementor-widget elementor-widget-image\" data-id=\"adfa2c0\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t\t\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img fetchpriority=\"high\" decoding=\"async\" width=\"1024\" height=\"546\" src=\"https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653a03e66ddf492197636386-1024x546.jpg\" class=\"attachment-large size-large wp-image-264\" alt=\"\" srcset=\"https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653a03e66ddf492197636386-1024x546.jpg 1024w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653a03e66ddf492197636386-300x160.jpg 300w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653a03e66ddf492197636386-768x410.jpg 768w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653a03e66ddf492197636386-1536x819.jpg 1536w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653a03e66ddf492197636386.jpg 2000w\" sizes=\"(max-width: 1024px) 100vw, 1024px\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">Cited from\uff1aIntegrating Genetic Alterations and the Hippo Pathway in Head and Neck Squamous Cell Carcinoma for Future Precision Medicine. Ando T et al, J Pers Med, 12(10):1544, 2022. <\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-413258d e-flex e-con-boxed e-con e-parent\" data-id=\"413258d\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-bab114b elementor-widget elementor-widget-text-editor\" data-id=\"bab114b\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t\t\t\t\t\t<p data-start=\"71\" data-end=\"469\">The <strong data-start=\"75\" data-end=\"92\">Hippo pathway<\/strong> plays a central role in regulating cell proliferation and the development of tissues and organs. It consists primarily of the serine\/threonine kinases <strong data-start=\"244\" data-end=\"292\">MST1\/2 (mammalian STE20-like kinase 1 and 2)<\/strong> and <strong data-start=\"297\" data-end=\"341\">LATS1\/2 (large tumor suppressor 1 and 2)<\/strong>, along with their respective adaptor proteins, <strong data-start=\"389\" data-end=\"418\">SAV1 (Salvador homolog 1)<\/strong> and <strong data-start=\"423\" data-end=\"468\">MOB1A\/B (MOB kinase activators 1A and 1B)<\/strong>.<\/p><p data-start=\"471\" data-end=\"1175\">Downstream of this pathway lie the key effectors <strong data-start=\"520\" data-end=\"552\">YAP (Yes-associated protein)<\/strong> and <strong data-start=\"557\" data-end=\"618\">TAZ (transcriptional co-activator with PDZ binding motif)<\/strong>. When the Hippo pathway is activated, LATS1\/2 phosphorylate YAP\/TAZ at five serine residues, resulting in their sequestration in the cytoplasm or degradation via the ubiquitin-proteasome system. Conversely, when the Hippo pathway is inactivated, dephosphorylated YAP\/TAZ translocate into the nucleus, where they bind to <strong data-start=\"939\" data-end=\"989\">TEAD (TEA domain family) transcription factors<\/strong> and act as co-activators to promote the expression of proliferation-related genes such as <strong data-start=\"1080\" data-end=\"1122\">CTGF (connective tissue growth factor)<\/strong> and <strong data-start=\"1127\" data-end=\"1174\">CYR61 (cysteine-rich angiogenic inducer 61)<\/strong>.<\/p><p data-start=\"1177\" data-end=\"1483\">YAP\/TAZ activity is regulated by physiological factors such as <strong data-start=\"1240\" data-end=\"1256\">cell density<\/strong>, <strong data-start=\"1258\" data-end=\"1279\">mechanical stress<\/strong>, and <strong data-start=\"1285\" data-end=\"1307\">serum availability<\/strong>. In addition, upstream regulators include <strong data-start=\"1350\" data-end=\"1389\">GPCRs (G protein-coupled receptors)<\/strong> and <strong data-start=\"1394\" data-end=\"1423\">receptor tyrosine kinases<\/strong>, which modulate the Hippo pathway under various conditions.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-3ed390e e-flex e-con-boxed e-con e-parent\" data-id=\"3ed390e\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-295448e elementor-widget elementor-widget-heading\" data-id=\"295448e\" data-element_type=\"widget\" data-widget_type=\"heading.default\">\n\t\t\t\t\t<h2 class=\"elementor-heading-title elementor-size-default\">Significance of the Hippo Pathway in Oral Squamous Cell Carcinoma<\/h2>\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-0424682 e-flex e-con-boxed e-con e-parent\" data-id=\"0424682\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-d95610c elementor-widget__width-initial elementor-widget elementor-widget-image\" data-id=\"d95610c\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t<img decoding=\"async\" width=\"1024\" height=\"772\" src=\"https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/666315845c7fa828544178c1-1024x772.jpg\" class=\"attachment-large size-large wp-image-171\" alt=\"\" srcset=\"https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/666315845c7fa828544178c1-1024x772.jpg 1024w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/666315845c7fa828544178c1-300x226.jpg 300w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/666315845c7fa828544178c1-768x579.jpg 768w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/666315845c7fa828544178c1.jpg 1296w\" sizes=\"(max-width: 1024px) 100vw, 1024px\" \/>\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<div class=\"elementor-element elementor-element-73dc9eb elementor-widget__width-initial elementor-widget elementor-widget-text-editor\" data-id=\"73dc9eb\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t\t\t\t\t\t<p data-start=\"144\" data-end=\"402\">We have demonstrated that various genetic alterations in <strong data-start=\"201\" data-end=\"240\">oral squamous cell carcinoma (OSCC)<\/strong> lead to inactivation of the <strong data-start=\"269\" data-end=\"286\">Hippo pathway<\/strong>, resulting in aberrant activation of <strong data-start=\"324\" data-end=\"335\">YAP\/TAZ<\/strong>, key transcriptional co-activators involved in cell proliferation.<\/p><p data-start=\"404\" data-end=\"672\">We previously showed that <strong data-start=\"430\" data-end=\"483\">Tissue Inhibitor of Metalloproteinases-1 (TIMP-1)<\/strong> is overexpressed in OSCC and promotes YAP\/TAZ activation through interactions with <strong data-start=\"567\" data-end=\"575\">CD63<\/strong> and <strong data-start=\"580\" data-end=\"593\">integrins<\/strong>, thereby enhancing tumor cell proliferation (Ando T et al., <em data-start=\"654\" data-end=\"664\">Oncogene<\/em>, 2017).<\/p><p data-start=\"674\" data-end=\"1178\"><strong data-start=\"674\" data-end=\"717\">Epidermal Growth Factor Receptor (EGFR)<\/strong> plays a central role in cell proliferation through ligand-induced dimerization and autophosphorylation, triggering downstream signaling cascades. In OSCC, EGFR is frequently amplified and overexpressed. We demonstrated that EGFR phosphorylates three tyrosine residues on <strong data-start=\"989\" data-end=\"997\">MOB1<\/strong>, a key component of the Hippo pathway, leading to <strong data-start=\"1048\" data-end=\"1075\">inactivation of LATS1\/2<\/strong> and subsequent <strong data-start=\"1091\" data-end=\"1116\">activation of YAP\/TAZ<\/strong>, promoting tumor growth (Ando T et al., <em data-start=\"1157\" data-end=\"1170\">Commun Biol<\/em>, 2021).<\/p><p data-start=\"1180\" data-end=\"1994\">Although <strong data-start=\"1189\" data-end=\"1208\">EGFR inhibitors<\/strong> have been approved as molecular targeted therapies for OSCC, their clinical efficacy is limited, and resistance remains a major issue. Previous studies have suggested that reactivation of YAP and upregulation of other <strong data-start=\"1427\" data-end=\"1463\">receptor tyrosine kinases (RTKs)<\/strong> may contribute to this resistance. We hypothesized that a specific RTK may drive YAP reactivation after transient inhibition by EGFR inhibitors. Through our investigation, we identified <strong data-start=\"1650\" data-end=\"1657\">AXL<\/strong> as a novel RTK that activates YAP via the EGFR\u2013LATS1\/2 axis. Notably, the combined use of EGFR and AXL inhibitors led to <strong data-start=\"1779\" data-end=\"1812\">sustained inactivation of YAP<\/strong> and marked <strong data-start=\"1824\" data-end=\"1855\">suppression of tumor growth<\/strong>, underscoring the therapeutic potential of dual inhibition or direct YAP targeting in resistant OSCC (Okamoto K et al., <em data-start=\"1976\" data-end=\"1986\">Oncogene<\/em>, 2023).<\/p><p data-start=\"1996\" data-end=\"2796\">In recent years, nuclear interactions of YAP\/TAZ have garnered increasing attention, but their OSCC-specific binding partners remained unclear. We identified <strong data-start=\"2154\" data-end=\"2163\">RBM39<\/strong>, an RNA-binding protein, as a YAP interactor that enhances YAP\/TEAD transcriptional activity. Interestingly, <strong data-start=\"2273\" data-end=\"2286\">indisulam<\/strong>, a compound known to degrade RBM39, induces both transcriptional repression and aberrant splicing, leading to cell death. However, when YAP binds to RBM39, it delays RBM39 degradation and mitigates both transcriptional repression and splicing disruption, conferring <strong data-start=\"2553\" data-end=\"2580\">resistance to indisulam<\/strong>. We are currently investigating the structural basis of the YAP\u2013RBM39 interaction with the goal of developing novel therapeutics that disrupt this oncogenic axis (Ando T et al., <em data-start=\"2759\" data-end=\"2772\">Oncogenesis<\/em>, 2024).<\/p><p data-start=\"2798\" data-end=\"3822\">To sustain growth, cancer cells must evade immune surveillance. Tumors with a high <strong data-start=\"2881\" data-end=\"2914\">tumor mutational burden (TMB)<\/strong> tend to produce <strong data-start=\"2931\" data-end=\"2946\">neoantigens<\/strong>, attracting cytotoxic T cells. However, cancer cells can evade immune attack by expressing <strong data-start=\"3038\" data-end=\"3047\">PD-L1<\/strong>, which binds to <strong data-start=\"3064\" data-end=\"3072\">PD-1<\/strong> on T cells and suppresses their activity. The link between the <strong data-start=\"3136\" data-end=\"3172\">Hippo pathway and immune evasion<\/strong>, however, has been unclear. Our recent findings suggest that <strong data-start=\"3234\" data-end=\"3350\">patients with genetic alterations in Hippo pathway components may respond better to immune checkpoint inhibitors<\/strong> such as anti\u2013PD-1 antibodies. Activation of YAP\/TAZ promotes <strong data-start=\"3412\" data-end=\"3435\">genomic instability<\/strong>, leading to increased TMB and T-cell recruitment. At the same time, YAP\/TAZ also upregulate <strong data-start=\"3528\" data-end=\"3551\">PD-L2 transcription<\/strong>, contributing to immune evasion. These opposing roles may explain the enhanced sensitivity to PD-1 blockade therapy. We are now expanding our investigation into how Hippo-YAP\/TAZ signaling shapes the <strong data-start=\"3752\" data-end=\"3785\">tumor immune microenvironment<\/strong> (Ando T et al., under review, 2025).<\/p><p data-start=\"3824\" data-end=\"4069\">In summary, although many genetic alterations that inactivate the Hippo pathway have been identified in OSCC, further research is needed to fully elucidate the mechanisms by which this pathway drives tumor progression and therapeutic resistance.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-3ad7d2c e-flex e-con-boxed e-con e-parent\" data-id=\"3ad7d2c\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-02e1ad5 elementor-widget elementor-widget-heading\" data-id=\"02e1ad5\" data-element_type=\"widget\" data-widget_type=\"heading.default\">\n\t\t\t\t\t<h2 class=\"elementor-heading-title elementor-size-default\">Targeting the Hippo\u2013YAP\/TAZ Pathway for Diagnosis and Therapy in Oral Cancer<\/h2>\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-f9dcab8 e-flex e-con-boxed e-con e-parent\" data-id=\"f9dcab8\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-d722914 elementor-widget__width-initial elementor-widget elementor-widget-image\" data-id=\"d722914\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t\t\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img decoding=\"async\" width=\"949\" height=\"1024\" src=\"https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653dfc1d26c02221e816f8ed-1-949x1024.jpg\" class=\"attachment-large size-large wp-image-266\" alt=\"\" srcset=\"https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653dfc1d26c02221e816f8ed-1-949x1024.jpg 949w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653dfc1d26c02221e816f8ed-1-278x300.jpg 278w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653dfc1d26c02221e816f8ed-1-768x828.jpg 768w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653dfc1d26c02221e816f8ed-1-1424x1536.jpg 1424w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653dfc1d26c02221e816f8ed-1-1899x2048.jpg 1899w, https:\/\/oralpathology.hiroshima-u.ac.jp\/wp-content\/uploads\/2025\/07\/653dfc1d26c02221e816f8ed-1.jpg 2000w\" sizes=\"(max-width: 949px) 100vw, 949px\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">Cited from\uff1aIntegrating Genetic Alterations and the Hippo Pathway in Head and Neck Squamous Cell Carcinoma for Future Precision Medicine. Ando T et al, J Pers Med, 12(10):1544, 2022. <\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-596612d e-flex e-con-boxed e-con e-parent\" data-id=\"596612d\" data-element_type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-33b01df elementor-widget elementor-widget-text-editor\" data-id=\"33b01df\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t\t\t\t\t\t<p data-start=\"88\" data-end=\"219\">The detailed mechanisms by which specific genetic alterations lead to <strong data-start=\"158\" data-end=\"195\">inactivation of the Hippo pathway<\/strong> remain largely unclear.<\/p><p data-start=\"221\" data-end=\"670\">As a result, cancer genome profiling may reveal genetic alterations that <em data-start=\"294\" data-end=\"307\">potentially<\/em> affect the Hippo\u2013YAP\/TAZ signaling axis, yet their functional consequences are still unknown\u2014making it difficult to translate such findings into therapeutic applications. Even when known alterations that inactivate the Hippo pathway are identified, there are currently <strong data-start=\"577\" data-end=\"621\">no approved molecular targeted therapies<\/strong> that directly inhibit the Hippo\u2013YAP\/TAZ pathway.<\/p><p data-start=\"672\" data-end=\"891\">One promising therapeutic candidate is <strong data-start=\"711\" data-end=\"730\">TEAD inhibitors<\/strong>, which disrupt the interaction between YAP and TEAD by binding to a defined pocket within TEAD, thereby blocking transcriptional activation of YAP target genes.<\/p><p data-start=\"893\" data-end=\"1181\">Our ongoing research aims to uncover the molecular links between <strong data-start=\"958\" data-end=\"1021\">genetic alterations and Hippo\u2013YAP\/TAZ pathway dysregulation<\/strong>, while also working toward the development of <strong data-start=\"1068\" data-end=\"1122\">next-generation diagnostics and targeted therapies<\/strong> that specifically address this critical oncogenic pathway.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t","protected":false},"excerpt":{"rendered":"<p>Research Overview \u304a\u4f7f\u3044\u306e\u30d6\u30e9\u30a6\u30b6\u3067\u306f\u52d5\u753b\u304c\u518d\u751f\u3067\u304d\u307e\u305b\u3093\u3002 Genetic alterations and cell signaling research Understanding Cancer \u2014 [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-596","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/oralpathology.hiroshima-u.ac.jp\/index.php\/wp-json\/wp\/v2\/pages\/596","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/oralpathology.hiroshima-u.ac.jp\/index.php\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/oralpathology.hiroshima-u.ac.jp\/index.php\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/oralpathology.hiroshima-u.ac.jp\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/oralpathology.hiroshima-u.ac.jp\/index.php\/wp-json\/wp\/v2\/comments?post=596"}],"version-history":[{"count":15,"href":"https:\/\/oralpathology.hiroshima-u.ac.jp\/index.php\/wp-json\/wp\/v2\/pages\/596\/revisions"}],"predecessor-version":[{"id":864,"href":"https:\/\/oralpathology.hiroshima-u.ac.jp\/index.php\/wp-json\/wp\/v2\/pages\/596\/revisions\/864"}],"wp:attachment":[{"href":"https:\/\/oralpathology.hiroshima-u.ac.jp\/index.php\/wp-json\/wp\/v2\/media?parent=596"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}