Why do certain genetic changes cause cancer only in certain organs of the human body? Scientists at the German Cancer Consortium (DKTK), Technische Universität München (TUM), and the University Medical Center Göttingen have demonstrated that cells from different organs are differently susceptible to activating mutations in cancer drivers: progenitors. Same mutations in cells Changes in the pancreas or bile duct lead to radically different consequences. For the first time, the team discovered that tissue-specific genetic interactions are responsible for the differences in bile duct and pancreatic epithelial susceptibility to oncogene transformation. New discoveries may lead to more accurate therapeutic decisions in the future.
There was no significant improvement in pancreas and pancreatic treatment Biliary tract cancer In the last few decades, effective targeted therapies have not been available to date. “The situation in patients with pancreatic and extrahepatic cholangiocarcinoma is still very depressing, with only about 10% of patients surviving for 5 years,” said DKTK Translated Cancer Research Professor at TUM University Hospital Klinikum rechts der Isar. Dieter Saur says. Munich.
DKTK is a consortium centered around the German Cancer Research Center (DKFZ) in Heidelberg and has long-term partnerships with specialized oncology centers at universities throughout Germany.
“To discover new therapeutic strategies that improve the prognosis of these patients, it is essential to understand the underlying genetic networks and interactions that drive these tumors in a tissue-specific manner. Very accurate molecular intervention is possible. “
The researchers investigated the development of biliary and pancreatic cancers in mice and replaced the normal oncogenes PIK3CA and KRAS with versions that contained the same mutations as human cancers. Expression of these oncogenes in common progenitor cells of the extrahepatic bile duct and pancreas yielded very different results. Mice carrying the mutated PI3K gene primarily developed biliary tract cancer, and mice carrying the mutated KRAS gene instead developed only pancreatic cancer.
This was unexpected because both genes are mutated in both human cancer types. Subsequent analysis revealed the underlying genetic processes that underlie the differences in susceptibility of different tissue types to carcinogenic transformation.
“Our results are an important step in solving one of the greatest mysteries of oncology. Why do changes in certain genes cause cancer only in certain organs?” New publication Says Chiara Falcomatà, the first author of. “Our studies in mice have revealed how genes work together to cause cancer in different organs, threatening key players, the order in which tumors develop during progression, and normal cells. Identified the molecular process that transforms cancer into new therapeutic targets. “
In mice, the team revealed a step-by-step process of genetic alteration that promotes the development of these types of cancer. Some collaborative genetic events overactivate PI3K signaling pathways and make them cancerous. Others destroy regulatory proteins and inactivate their ability to control the progression of cancer.
“Understanding the genetic interactions of different types of cancer will enable more accurate therapeutic decisions in the future,” said Gunter Schneider, a professor of translational cancer research at the University of Göttingen Medical Center. Says. “The ability to manipulate specific genetic alterations in mice allows us to study the function of oncogenes and model specific cancer subtypes. Such mouse models are antineoplastic agents before they are used in clinical trials. It is also very valuable for testing. “
“We have shown that the function of oncogenes depends on the type of tissue and which other genes are altered,” said Professor Roland Rad of TUM and researchers at DKTK. “These oncogenes need to hijack the unique signal transduction networks of specific tissues to enable the development of cancer. Interestingly, such networks exist only in specific tissue types and cancer. Is more susceptible to outbreaks. “
These findings have important implications for therapeutic intervention. “The concept that multiple tissue-specific genetic interactions promote cancer progression shows that a single gene cannot predict cancer responsiveness. cancer “For a particular treatment,” Saur said. “In the future, it is important to mechanically understand the tissue-specific determinants of therapeutic response and resistance to take precision medicine to the next level.”
Some of the authors, including Dieter Saur and Roland Rad, are based at Transla TUM, TUM’s Center for Translation Cancer Research. At this interdisciplinary laboratory, doctors work with colleagues in the natural sciences and engineering fields to study the causes, diagnoses, and potential treatments for cancerous diseases.
Chiara Falcomata et al, genetic screening, identifies situation-specific PI3K / p27Kip1 nodes that cause extrahepatic cholangiocarcinoma. Cancer detection (2021). DOI: 10.1158 / 2159-8290.CD-21-0209
German Cancer Research Center
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Why the same mutation causes different types of cancer
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