Why do mutations in particular genes only cause cancer in certain organs of the human body? Scientists from the German Cancer Consortium (DKTK), the Technical University of Munich (TUM), and the University Medical Center Göttingen have now shown that cells from various organs are susceptible to cancer driver activating mutations in distinct ways: The identical mutation in pancreatic precursor cells or bile duct precursor cells results in fundamentally different consequences. The researchers revealed for the first time that tissue-specific genetic connections are responsible for the biliary and pancreatic epithelium’s differential sensitivity to oncogene transformation. In the future, the new results might help doctors make more accurate therapy decisions.
In the previous several decades, there have been no significant advancements in the treatment of pancreatic and biliary tract cancer, and no effective targeted treatments are now available. Dieter Saur, DKTK Professor for Translational Cancer Research at TUM’s university hospital Klinikum rechts der Isar, DKTK partner site Munich, says, “The situation for patients with pancreatic and extrahepatic bile duct cancer is still very depressing, with approximately only 10% of patients surviving five years.”
DKTK is a collaboration headquartered on Heidelberg’s German Cancer Research Center (DKFZ), which maintains long-term cooperation agreements with specialist oncological facilities at universities around Germany.
“Understanding the basic genetic networks and interactions that drive these cancers in a tissue-specific manner is critical for developing innovative treatment methods that improve prognosis for these patients. In the future, this will allow for very precise molecular interventions.”
The researchers studied the progression of biliary tract and pancreatic cancer in mice by substituting the normal “oncogenes” PIK3CA and KRAS with a version carrying a mutation similar to that found in human malignancies. When these oncogenes were expressed in the shared progenitor cells of the extrahepatic bile duct and the pancreas, the results were quite different. Mice with a mutant PI3K gene produced mainly biliary tract cancer, whereas mice with a mutated KRAS gene developed pancreatic cancer exclusively.
This was surprising because both genes are mutated in both kinds of human cancer. Following that, the fundamental genetic mechanisms underpinning the variable susceptibility of various tissue types to neoplastic transformation were identified.
“Our findings represent a significant step toward resolving one of oncology’s most vexing questions: why can mutations in certain genes exclusively cause cancer in specific organs?” According to Chiara Falcomatà, the book’s initial author. “Our mouse experiments demonstrated how genes work together to generate cancer in many tissues. We identified key actors, the sequence in which they appear throughout tumor growth, and the molecular mechanisms that transform healthy cells into cancerous tumors. These mechanisms might be used as targets for future treatments.”
The researchers discovered a step-by-step mechanism of genetic changes in mice that drives the development of various cancer kinds. Some cooperative genetic events cause the PI3K signaling pathway to become overactive, resulting in cancer. Others inactivate the capacity of regulator proteins to inhibit cancer development by disrupting them.
“Understanding the genetic connections in various cancer types will lead to more accurate treatment decision-making in the future,” says Günter Schneider, Professor for Translational Cancer Research at the University Medical Center Göttingen. “We can examine the function of cancer genes and simulate distinct cancer subtypes thanks to our capacity to create precise genetic changes in mice. Anticancer medicines can also be tested in these mice models before being used in human trials.”
“What we found is that an oncogene’s function varies depending on the tissue type and other genes altered,” says Roland Rad, a TUM professor and DKTK researcher. “In order for cancer to grow, these oncogenes must hijack the intrinsic signaling network of a given tissue. Surprisingly, such networks are found only in particular tissue types, rendering them vulnerable to the development of cancer.”
The ramifications of these results for therapeutic treatments are significant. “The idea that cancer development is driven by numerous tissue-specific genetic interactions indicates that no one gene can predict a tumour’s response to a particular therapy,” Saur adds. “To take precision medicine to the next level, it will be critical to mechanistically understand the tissue specific drivers of treatment response and resistance.”
Dieter Saur and Roland Rad, two of the authors, work at TranslaTUM, TUM’s Center for Translational Cancer Research. Doctors collaborate with colleagues from the disciplines of natural sciences and engineering on research into the causes, diagnosis, and potential therapies of malignant illnesses at this multidisciplinary research institution.