Why Identical Genetic Mutations Cause Different Types of Cancer

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Pancreatic Cancer

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Pancreatic Cancer, caused by activation of the PIK3CA oncogene. Credit: T. Santos/DKTK & TUM

Why do modifications of particular genes trigger cancer just in particular organs of the body? Scientists at the German Cancer Consortium (DKTK), the Technical University of Munich (TUM), and the University Medical Center Göttingen have actually now shown that cells stemming from various organs are differentially prone to triggering anomalies in cancer motorists: The exact same anomaly in precursor cells of the pancreas or the bile duct results in essential various results. The group found for the very first time that tissue particular hereditary interactions are accountable for the differential vulnerability of the biliary and the pancreatic epithelium towards improvement by oncogenes. The brand-new findings might assist more exact restorative choice making in the future.

There have actually been no significant enhancements in the treatment of pancreatic and biliary system cancer in the last years and no reliable targeted treatments are offered to date. “The situation for patients with pancreatic and extrahepatic bile duct cancer is still very depressing with approximately only 10% of patients surviving five years,” states Dieter Saur, DKTK Professor for Translational Cancer Research at TUM’s university health center Klinikum rechts der Isar, DKTK partner website Munich.

DKTK is a consortium focused around the German Cancer Research Center (DKFZ) in Heidelberg, which has long-lasting collective collaborations with professional oncological centers at universities throughout Germany.

“To discover novel therapeutic strategies that improve prognosis of these patients, it is essential to understand the fundamental genetic networks and interactions that drive these tumors in a tissue-specific fashion. This will allow highly precise molecular interventions in future.”

The research study group took a look at the advancement of biliary system and pancreatic cancer in mice, changing the typical “oncogenes” PIK3CA and KRAS with a variation including an anomaly similar with that in human cancers. Expression of these oncogenes in the typical precursor cells of the extrahepatic bile duct and the pancreas resulted in extremely various results. Mice with the altered PI3K gene established primarily biliary system cancer, mice with the altered KRAS gene rather established solely pancreatic cancer.

This was unanticipated due to the fact that both genes are altered in both human cancer types. Subsequent analyses found the essential hereditary procedures underlying the differential level of sensitivity of the various tissue types towards oncogenic improvement.

“Our results are an important step toward solving one of the biggest mysteries in oncology: Why do alterations of certain genes cause cancer only in specific organs?” states Chiara Falcomatà the very first author of the brand-new publication. “Our studies in mice revealed how genes co-operate to cause cancer in different organs. We identified main players, the order in which they occur during tumor progression, and the molecular processes how they turn normal cells into threatening cancers. Such processes are potential targets for new treatments”.

In the mice, the group revealed a step-by-step procedure of hereditary modifications, which drive the advancement of these cancer types. Some working together hereditary occasions overactivate the PI3K signaling path, making them malignant. Others interfere with regulators proteins, suspending their capability to reduce cancer development.

“Understanding the genetic interactions in different cancer types will guide more precise therapeutic decision making in the future,” states Günter Schneider, Professor for Translational Cancer Research at the University Medical Center Göttingen. “Our ability to engineer specific genetic alterations in mice allows us to study the function of cancer genes and to model specific cancer subtypes. Such mouse models are also invaluable for testing anticancer drugs before using them in clinical trials”.

“What we showed is that the function of an oncogene is different depending on the tissue type and what other genes are altered,” states Roland Rad Professor at TUM and a DKTK scientist. “These oncogenes need to hijack the intrinsic signaling network of a specific tissue to allow cancer development. Interestingly, such networks exist only in specific tissue types making them susceptible for cancer development.”

These findings have essential ramifications for restorative interventions. “The concept that multiple tissue-specific genetic interactions drive cancer progression demonstrates that no single gene can predict responsiveness of a cancer to a particular therapy,” states Saur. “In future, it is key to mechanistically understand the tissue specific determinants of therapeutic response and resistance to get precision medicine to the next level.”

Several of the authors consisting of Dieter Saur and Roland Rad are based at TranslaTUM, TUM’s Center for Translational Cancer Research. In this interdisciplinary research study institute, medical professionals deal with coworkers from the fields of lives sciences and engineering on research study into causes, diagnostics and possible treatments of malignant illness.

Reference: “Genetic screens identify a context-specific PI3K/p27Kip1 node driving extrahepatic biliary cancer” by Chiara Falcomata, Stefanie Barthel, Angelika Ulrich, Sandra Diersch, Christian Veltkamp, Lena Rad, Fabio Boniolo, Myriam Solar, Katja Steiger, Barbara Seidler, Magdalena Zukowska, Joanna Madej, Mingsong Wang, Rupert Ollinger, Roman Maresch, Maxim Barenboim, Stefan Eser, Markus Tschurtschenthaler, Arianeb Mehrabi, Stephanie Roessler, Benjamin Goeppert, Alexander Kind, Angelika Schnieke, Maria S Robles, Allan Bradley, Roland M Schmid, Marc Schmidt-Supprian, Maximilian Reichert, Wilko Weichert, Owen J Sansom, Jennifer P Morton, Roland Rad, Gunter Schneider and Dieter Saur, 19 July 2021, Cancer Discovery.
DOI: 10.1158/2159-8290.CD-21-0209

Chiara Falcomatà, Stefanie Bärthel, Angelika Ulrich, Sandra Diersch, Christian Veltkamp, Lena Rad, Fabio Boniolo, Myriam Solar, Katja Steiger, Barbara Seidler, Magdalena Zukowska, Joanna Madej, Mingsong Wang, Rupert Öllinger, Roman Maresch, Maxim Barenboim, Stefan Eser, Markus Tschurtschenthaler, Arianeb Mehrabi, Stephanie Roessler, Benjamin Goeppert, Alexander Kind, Angelika Schnieke, Maria S. Robles, Allan Bradley, Roland M. Schmid, Marc Schmidt-Supprian, Maximilian Reichert, Wilko Weichert, Owen J. Sansom, Jennifer P. Morton, Roland Rad, Günter Schneider, Dieter Saur: Genetic screens determine a context-specific PI3K/p27Kip1 node driving extrahepatic biliary cancer

 



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