CINXE.COM

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Over the last two decades, scientists have observed that many cancers progress by activating a set of proteins called YAP and TAZ, which control cell growth and organ size. When left uncontrolled, YAP/TAZ can lead to tumor formation. So, if you’re looking for new drug targets, why..." /> <meta property="og:url" content="https://www.cshl.edu/flipping-cancers-off-switch/" /> <meta property="og:site_name" content="Cold Spring Harbor Laboratory" /> <meta property="article:publisher" content="https://www.facebook.com/cshlnews" /> <meta property="article:published_time" content="2024-11-07T12:30:54+00:00" /> <meta property="article:modified_time" content="2024-11-07T13:39:39+00:00" /> <meta property="og:image" content="https://www.cshl.edu/wp-content/uploads/2024/10/Lung_cancer_cells_MARK2-3.jpg" /> <meta property="og:image:width" content="1920" /> <meta property="og:image:height" content="1080" /> <meta property="og:image:type" content="image/jpeg" /> <meta name="author" content="Sara Giarnieri" /> <meta name="twitter:card" content="summary_large_image" /> <meta name="twitter:creator" content="@CSHL" /> <meta name="twitter:site" content="@CSHL" /> <meta name="twitter:label1" content="Written by" /> <meta name="twitter:data1" content="Sara Giarnieri" /> <meta name="twitter:label2" content="Est. reading time" /> <meta name="twitter:data2" content="2 minutes" /> <script type="application/ld+json" class="yoast-schema-graph">{"@context":"https://schema.org","@graph":[{"@type":"Article","@id":"https://www.cshl.edu/flipping-cancers-off-switch/#article","isPartOf":{"@id":"https://www.cshl.edu/flipping-cancers-off-switch/"},"author":{"name":"Sara Giarnieri","@id":"https://www.cshl.edu/#/schema/person/8a6b52dd303010dd5c223d95ec921655"},"headline":"Flipping cancer’s off switch","datePublished":"2024-11-07T12:30:54+00:00","dateModified":"2024-11-07T13:39:39+00:00","mainEntityOfPage":{"@id":"https://www.cshl.edu/flipping-cancers-off-switch/"},"wordCount":396,"publisher":{"@id":"https://www.cshl.edu/#organization"},"image":{"@id":"https://www.cshl.edu/flipping-cancers-off-switch/#primaryimage"},"thumbnailUrl":"https://www.cshl.edu/wp-content/uploads/2024/10/Lung_cancer_cells_MARK2-3.jpg","keywords":["breast cancer","cancer","cancer research","Christopher Vakoc","core facility","CRISPR","lung cancer","pancreas/pancreatic cancer","pediatric cancer","sarcoma"],"articleSection":["Research"],"inLanguage":"en-US"},{"@type":"WebPage","@id":"https://www.cshl.edu/flipping-cancers-off-switch/","url":"https://www.cshl.edu/flipping-cancers-off-switch/","name":"Flipping cancer’s off switch | Cold Spring Harbor Laboratory","isPartOf":{"@id":"https://www.cshl.edu/#website"},"primaryImageOfPage":{"@id":"https://www.cshl.edu/flipping-cancers-off-switch/#primaryimage"},"image":{"@id":"https://www.cshl.edu/flipping-cancers-off-switch/#primaryimage"},"thumbnailUrl":"https://www.cshl.edu/wp-content/uploads/2024/10/Lung_cancer_cells_MARK2-3.jpg","datePublished":"2024-11-07T12:30:54+00:00","dateModified":"2024-11-07T13:39:39+00:00","breadcrumb":{"@id":"https://www.cshl.edu/flipping-cancers-off-switch/#breadcrumb"},"inLanguage":"en-US","potentialAction":[{"@type":"ReadAction","target":["https://www.cshl.edu/flipping-cancers-off-switch/"]}]},{"@type":"ImageObject","inLanguage":"en-US","@id":"https://www.cshl.edu/flipping-cancers-off-switch/#primaryimage","url":"https://www.cshl.edu/wp-content/uploads/2024/10/Lung_cancer_cells_MARK2-3.jpg","contentUrl":"https://www.cshl.edu/wp-content/uploads/2024/10/Lung_cancer_cells_MARK2-3.jpg","width":1920,"height":1080,"caption":"When MARK2/3 proteins are knocked out in cancer cells, fewer cancer-promoting YAP proteins (red) make their way to the cell nuclei. 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href="https://www.cshl.edu/news-stand/">Newsstand</a> / <a href="https://www.cshl.edu/news-stand/cshl-stories/">CSHL Stories and Media</a></span></p> </div> </div> <article id="post-72120" class="post-72120 post type-post status-publish format-standard has-post-thumbnail hentry category-research tag-breast-cancer tag-cancer tag-cancer-research tag-christopher-vakoc tag-core-facility tag-crispr tag-lung-cancer tag-pancreas-pancreatic-cancer tag-pediatric-cancer tag-sarcoma">  <header> <div class="row"> <div class="col-lg-10 col-lg-offset-1 col-lg-offset-right-1 col-md-12 col-sm-12 col-xs-12"> <h1>Flipping cancer’s off switch</h1> </div> </div> </header>  <div class="row area-start"> <div class="col-lg-10 col-lg-offset-1 col-lg-offset-right-1 col-md-12 col-sm-12 col-xs-12"> <img class="img-responsive" src="https://www.cshl.edu/wp-content/uploads/2024/10/Lung_cancer_cells_MARK2-3.jpg" alt="image of Lung Cancer cells" /><figcaption class="cshl-post-caption">When MARK2/3 proteins are knocked out in cancer cells, fewer cancer-promoting YAP proteins (red) make their way to the cell nuclei. Above: lung cancer cells with (left) and without MARK2/3 (right). Note the decrease in YAP concentration on the right. </figcaption></div> </div> <div class="entry-content"> <div class="row"> <div class="col-lg-10 col-lg-offset-1 col-lg-offset-right-1 col-md-12 col-sm-12 col-xs-12"> <div class="entry-meta article-date top-margin-20 bottom-margin-25"><em> Read time 2 minutes | <span class="posted-on"><time class="entry-date published" datetime="Thursday, 7 November 2024">Thursday, 7 November 2024</time></span> </em> <div class='social-share-wrapper'><span class='email'><a href='mailto:?Subject=Flipping cancer’s off switch&Body=https://www.cshl.edu/flipping-cancers-off-switch/'><i class='fa-solid fa-square-envelope fa-3x social-share-icon ag-mail' aria-hidden='true'><span class='sr-only'>email envelop icon</span></i></a></span><span class='twitter'><a target='_blank' href='https://twitter.com/share?url=https://www.cshl.edu/flipping-cancers-off-switch/'><i class='fa-brands fa-square-x-twitter fa-3x social-share-icon x-twitter' aria-hidden='true'><span class='sr-only'>twitter icon share button</span></i></a></span><span class='facebook'><a target='_blank' href='http://www.facebook.com/sharer.php?u=https://www.cshl.edu/flipping-cancers-off-switch/'><i class='fa-brands fa-square-facebook fa-3x social-share-icon ag-facebook' aria-hidden='true'><span class='sr-only'>facebook icon share button</span></i></a></span><span class='linkedin'><a target='_blank' href='http://www.linkedin.com/shareArticle?url=https://www.cshl.edu/flipping-cancers-off-switch/'><i class='fa-brands fa-linkedin fa-3x social-share-icon ag-linkedin' aria-hidden='true'><span class='sr-only'>linkedin icon share button</span></i></a></span><div class='clear'></div></div> </div> </div> </div>  <div class="row area-start"> <div class="col-lg-7 col-lg-offset-1 col-md-8 col-sm-12 col-xs-12"> <div class="hidden-lg hidden-md print-yes"> <div class="takeaway-box print-yes"> <h4 class="orange-font print-yes">The Takeaway</h4> <p class="print-yes">CSHL Professor Christopher Vakoc and postdoc Olaf Klingbeil found that YAP and TAZ, a set of proteins that aid cancer progression, rely on a second set of proteins called MARK 2 and MARK 3. The discovery points to a potential drug target for some of the most common and deadly forms of cancer, as well as rarer forms like rhabdomyosarcoma.</p> </div> </div> <div class="printfriendly pf-button pf-button-content pf-alignleft"> <a href="#" rel="nofollow" onclick="window.print(); return false;" title="Printer Friendly, PDF & Email"> <img decoding="async" src="https://www.cshl.edu/wp-content/uploads/2023/03/print_pdf_icon.png" alt="Print Friendly, PDF & Email" class="pf-button-img" style="width: 124px;height: 36px;" /> </a> </div><p>If there’s one thing cancer knows, it’s growth. Over the last two decades, scientists have observed that many cancers progress by activating a set of proteins called YAP and TAZ, which control cell growth and organ size. When left uncontrolled, YAP/TAZ can lead to tumor formation. So, if you’re looking for new drug targets, why not start there? Targeting them directly, while possible, remains a challenge. Now, Cold Spring Harbor Laboratory Professor <a href="https://www.cshl.edu/research/faculty-staff/chris-vakoc/">Christopher Vakoc</a> and postdoc <a href="https://www.cshl.edu/research/postdoctoral-research/postdocs/olaf-klingbeil/">Olaf Klingbeil</a> have found a workaround. They’ve successfully tested their new approach in the lab against some of the most common and deadly cancers.</p> <p>Previous research aimed to target YAP/TAZ molecular interactions and directly inhibit their tumor-promoting function. Vakoc’s team wanted to find another way to go after them. Using a CRISPR screening strategy, they discovered that YAP and TAZ rely heavily on a second set of proteins called MARK 2 and MARK 3. Rather than interfering with the functions of YAP/TAZ directly, targeting MARK 2/3 reactivates their natural ‘off’ switch, called the Hippo signaling pathway.</p> <p>“We found a way to engage YAP/TAZ earlier,” Klingbeil says. “MARK 2/3 inhibition can reactivate a suppressor pathway normally used by healthy cells, thereby preventing them from going to the nucleus and being active.”</p> <p>Last year, Vakoc’s team transformed <a href="https://www.cshl.edu/once-rhabdomyosarcoma-now-muscle/">rhabdomyosarcoma</a> cells into healthy muscle cells—a major advancement. However, this treatment strategy, known as differentiation therapy, is still a long way from the clinic. MARK 2 and MARK 3, on the other hand, are druggable targets, and their activity in a wider range of tumors will hopefully generate interest among pharmaceutical companies. Vakoc explains:</p> <p><span class="soundcite" data-url="https://www.cshl.edu/wp-content/uploads/2024/10/Vakoc_target_rare_pediatric_sarcomas.mp3">“This is a target for rare pediatric sarcomas that we’re very passionate about trying to solve. It’s also relevant in breast cancer. It’s relevant in lung cancer. It’s relevant in pancreatic cancer. Some of the most common human cancers and uncommon human cancers share this addiction to YAP/TAZ.”</span></p> <p>Vakoc and Klingbeil found that by reactivating YAP/TAZ’s off switch, tumors don’t just stop growing. They actually shrink, and the cancer begins to disappear. The Vakoc lab now has a new drug target in its sights. In time, that could mean more effective treatments for thousands of patients and new hope for parents who want only to see their kids grow up healthy and cancer-free.</p> <p><strong>Written by</strong>: <a href="https://www.cshl.edu/author/giarnieri/">Sara Giarnieri</a>, <em>Social Media Specialist</em> | <a href="mailto:giarnieri@cshl.edu">giarnieri@cshl.edu</a> | 516-367-6842</p><hr><section id="funding"><p class="bottom-margin-10"><strong>Funding</strong></p><div class="printfriendly pf-button pf-button-content pf-alignleft"> <a href="#" rel="nofollow" onclick="window.print(); return false;" title="Printer Friendly, PDF & Email"><br /> <img decoding="async" src="https://www.cshl.edu/wp-content/uploads/2023/03/print_pdf_icon.png" alt="Print Friendly, PDF & Email" class="pf-button-img" style="width: 124px;height: 36px;" /><br /> </a> </div> <p>The Pershing Square Foundation, Sohn Conference Foundation, Simons Foundation, Thompson Foundation, Christina Renna Foundation, The Mary Ruchalski Foundation, Friends of T.J. Foundation, Michelle Paternoster Foundation, Daniela Conte Foundation, Maddie’s Promise Foundation, German Research Foundation, Lustgarten Foundation, CSHL-Northwell Health Affiliation, Northwell Health Tissue Donation Program, Cold Spring Harbor Laboratory Association, National Institutes of Health</p> </section><section id="citation"><p class="bottom-margin-10"><strong>Citation</strong></p><div class="printfriendly pf-button pf-button-content pf-alignleft"> <a href="#" rel="nofollow" onclick="window.print(); return false;" title="Printer Friendly, PDF & Email"><br /> <img decoding="async" src="https://www.cshl.edu/wp-content/uploads/2023/03/print_pdf_icon.png" alt="Print Friendly, PDF & Email" class="pf-button-img" style="width: 124px;height: 36px;" /><br /> </a> </div> <p>Klingbeil, O., <em>et al</em>., “MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer”, <em>Cancer Discovery</em>, July 26, 2024. DOI: <a href="https://doi.org/10.1158/2159-8290.CD-23-1529" target="_blank" rel="noopener">10.1158/2159-8290.CD-23-1529</a></p> </section> <section> <div class="well"><h4>Core Facilites</h4><div class="widget_text core-facility-sidebar"><div class="textwidget custom-html-widget"><a href="https://www.cshl.edu/research/cancer/mass-spectrometry-facility/"><img decoding="async" loading="lazy" class="alignleft size-full wp-image-2030" src="https://www.cshl.edu/wp-content/uploads/2017/07/mass_spectrometry_icon.png" alt=" " width="66" height="66" data-headline="mass_spectrometry_icon"></a> “The <a href="https://www.cshl.edu/research/cancer/mass-spectrometry-facility/">Mass Spectrometry Core Facility</a> provides state-of-the-art quantitative analysis of proteins and peptides, protein-protein interactions, and post-translational modifications. The resource also offers the ability to detect lipids, metabolites, and other small molecules. The facility supports experimental design, sample preparation, LC-MS analyses, and data analysis and interpretation.” — Director Paolo Cifani, Ph.D. </div></div><p class="clearfix"></p><div class="widget_text core-facility-sidebar"><div class="textwidget custom-html-widget"><a href="https://www.cshl.edu/research/cancer/sequencing-technologies-and-analysis/"><img decoding="async" loading="lazy" class="alignleft size-full wp-image-2034" src="https://www.cshl.edu/wp-content/uploads/2017/07/dna_sequencing_icon.png" alt="image of the sequencing core facility icon" width="66" height="66" data-headline="dna_sequencing_icon"></a> “The <a href="https://www.cshl.edu/research/cancer/sequencing-technologies-and-analysis/">Sequencing Technologies and Analysis Shared Resource</a> provides access to an array of high throughput Next Generation Sequencing (NGS) technologies. We offer cutting-edge technology alongside convenient in-house services for a broad range of genetic analysis.” — Project Manager Sara Goodwin, Ph.D.</div></div><p class="clearfix"></p></div></section> <div class="textwidget custom-html-widget"><div id="newsletter" class="panel panel-cshl"> <div class="panel-heading"> <h4> Stay informed </h4> </div> <div class="panel-body"> <p>Sign up for our newsletter to get the latest discoveries, upcoming events, videos, podcasts, and a news roundup delivered straight to your inbox every month. </p> <p class="text-center"><a href="https://www.cshl.edu/news-stand/newsletter/" class="btn btn-lg btn-learn-more-ag-gold"><span class="fa fa-envelope"></span>   Newsletter Signup</a></p> </div></div></div> </div>  <div class="col-lg-3 col-md-4 col-lg-offset-right-1 col-sm-12 col-xs-12"> <div class="hidden-sm hidden-xs print-no"> <div class="takeaway-box"> <h3 class="news-story">The Takeaway</h3> <p>CSHL Professor Christopher Vakoc and postdoc Olaf Klingbeil found that YAP and TAZ, a set of proteins that aid cancer progression, rely on a second set of proteins called MARK 2 and MARK 3. The discovery points to a potential drug target for some of the most common and deadly forms of cancer, as well as rarer forms like rhabdomyosarcoma.</p> </div> </div> <h3 class="news-story">Principal Investigator</h3><img class="img-responsive pi-headshot" alt ="Chris Vakoc" src="https://www.cshl.edu/wp-content/uploads/2022/03/Chris_Vakoc_profile.jpg"/><a href="https://www.cshl.edu/research/faculty-staff/chris-vakoc/"><h4>Chris Vakoc</h4></a> <p>Professor<br/>Alan and Edith Seligson Professor of Cancer Research<br/>Cancer Center Deputy Director of Research<br>M.D., Ph.D., University of Pennsylvania, 2007</p><h3>Tags</h3><div class="post-cloud"><a href="https://www.cshl.edu/tag/breast-cancer/" rel="tag">breast cancer</a> <a href="https://www.cshl.edu/tag/cancer/" rel="tag">cancer</a> <a href="https://www.cshl.edu/tag/cancer-research/" rel="tag">cancer research</a> <a href="https://www.cshl.edu/tag/christopher-vakoc/" rel="tag">Christopher Vakoc</a> <a href="https://www.cshl.edu/tag/core-facility/" rel="tag">core facility</a> <a href="https://www.cshl.edu/tag/crispr/" rel="tag">CRISPR</a> <a href="https://www.cshl.edu/tag/lung-cancer/" rel="tag">lung cancer</a> <a href="https://www.cshl.edu/tag/pancreas-pancreatic-cancer/" rel="tag">pancreas/pancreatic cancer</a> <a href="https://www.cshl.edu/tag/pediatric-cancer/" rel="tag">pediatric cancer</a> <a href="https://www.cshl.edu/tag/sarcoma/" rel="tag">sarcoma</a></div> <div>  </div>  </div> </article> <div class='yarpp yarpp-related yarpp-related-widget yarpp-template-yarpp-template-cshl-related-content'> <style> .related-content-tile { background: #ffffff; border: 1px solid rgb(212,212,212); height: 400px; overflow: hidden; position: relative; } .related-content-tile a:hover { text-decoration: none; } .related-content-teaser { color:#fff; position: absolute; top: 0; left: 0; width: 100%; background: rgb(0,73,130) !important; transition-property: all; transition-duration: .5s; 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left: 0; border: rgb(212,212,212) !important; font-family: 'Noto Serif',serif; } p.related-content-meta { margin-bottom:0; font-size:15px; } .related-content-meta a { border: rgb(212,212,212) !important; } .related-content-tile-img { margin-bottom: 10px; width: 100%; background-position: center center; background-size: cover; height:75%; } @media (max-width: 375px) { .related-content-tile-img { height:60%; } } @media (min-width: 992px) { .related-content-tile-img { height:55%; } } @media (min-width: 1200px) { .related-content-tile-img { height:65%; } } @media (min-width: 1367px) { .related-content-tile-img { height:60%; } } .yarpp-related h3 { font-size: 28px!important; line-height: 31px; font-weight:400!important; } </style> <hr /><h3>DISCOVER: Related stories</h3><div class="row"><a rel="external" href="https://www.cshl.edu/antioxidants-pro-cancer/"> <div class="col-md-4"><div class="related-content-tile"> <div class="related-content-tile-img" style="background-image:url(https://www.cshl.edu/wp-content/uploads/2017/10/BasePairs6-814x509.jpg)"></div><h4>When antioxidants are pro-cancer</h4><div class="related-content-teaser"><div class="related-content-teaser-content">For Pancreatic Cancer Awareness Month, <em>Base Pairs</em> looks at the science of antioxidants and cancer.   <strong>Read more »</strong></div></div><p class="related-content-meta">   <i class="fa fa-calendar-o"></i> November 15, 2016</p></div></div></a><a rel="external" href="https://www.cshl.edu/cshl-organoid-facility-cancer-custodians/"> <div class="col-md-4"><div class="related-content-tile"> <div class="related-content-tile-img" style="background-image:url(https://www.cshl.edu/wp-content/uploads/2021/06/Camila_dosSantos_2L6A0157-814x458.jpg)"></div><h4>CSHL organoid facility: Cancer custodians</h4><div class="related-content-teaser"><div class="related-content-teaser-content">To beat our worst enemy, we must first let it grow.   <strong>Read more 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