Uncovering the molecular basis of pancreatic cancer metastasis
Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer and is predicted to become the second-leading cause of cancer-related deaths within the next decade. The average survival rate over five years is less than 10 %. Most patients have metastasis at the time of diagnosis, which is the major cause of death. Scientists have put significant effort into uncovering the genetic basis of PDAC, and international sequencing efforts have provided some key insights. Yet, genetic equivalent studies for metastasis have not been possible, in part due to a lack of tissue resources. Researchers in the PACA-MET project, which was funded by the European Research Council(opens in new window), sought to fill in this knowledge gap, through investigations into the genetic and molecular basis of metastasis. The project employed advanced sequencing and genome screens to uncover the genes and pathways that drive metastasis in mice. The researchers then validated newly discovered genes against human PDAC cohorts and functional studies in mice. Finally, they performed further in-depth mechanistic studies to identify the molecular networks responsible for driving metastasis in PDAC. “The key aim of the study was to uncover pancreatic ductal adenocarcinoma metastasis drivers and investigate the molecular mechanisms of their action,” explains Roland Rad, professor of Molecular Oncology and Functional Genomics at the Technical University of Munich. “Understanding the principles of cancer progression and metastasis opens new avenues for early interception and therapy.”
Rethinking pancreatic cancer metastasis
The project findings suggest that the molecular configuration of the initial tumour may determine metastasis in PDAC. “With few exceptions, primary tumours and their matched metastases displayed highly concordant molecular profiles,” notes Rad. This could have important implications for early risk stratification and therapeutic intervention. The team also discovered(opens in new window) a ‘metastasis’ switch(opens in new window), due to an imbalance in alleles following a specific mutation to a specific gene, KRAS. “This discovery establishes a mechanistic principle whereby quantitative changes in oncogenic signalling determine metastatic behaviour,” says Rad. “Importantly, our unpublished results indicate that this dosage-driven metastasis switch operates across multiple cancer types, establishing it as a broadly relevant biological principle.”
New drivers of disease progression
Other as yet unpublished results highlighted newly discovered drivers of disease progression. Through systematic screening, the team uncovered an unexpected, context-dependent anti-metastatic function of aneuploidy – a condition that results in an abnormal number of chromosomes. “Given that aneuploidy is widely regarded as a driver of tumour progression, this observation challenges established assumptions and introduces a more nuanced view of chromosomal instability in cancer evolution,” adds Rad. “Ongoing mechanistic work aims to define the underlying principles and dependencies of these observations.”
Enabling scientific advances around the world
Beyond conceptual advances, PACA-MET generated a comprehensive suite of broadly applicable genetic tools, screening platforms, computational methods as well as organismal and cell-based disease models. “These have been distributed to hundreds of laboratories worldwide and have already enabled numerous important discoveries across disciplines, with continued impact anticipated in the future,” notes Rad. “Together, they constitute a durable infrastructure resource and engine of discovery for the scientific community.” The researchers are now expanding their systematic analyses beyond genetics, integrating several research fields and advanced AI approaches. “We expect further fundamental discoveries, which will inform the development of therapeutic strategies,” says Rad.
