Periodic Reporting for period 4 - PACA-MET (Genome-wide surveys and functional analysis of pancreatic cancer metastasis drivers)
Periodo di rendicontazione: 2024-05-01 al 2025-10-31
Pancreatic cancer is one of the deadliest human malignancies. A major reason for its extremely poor prognosis is its tendency to metastasize—the spread of cancer cells from the primary tumor to distant organs—at a very early stage, often before the disease is even diagnosed. Although scientists have learned much about the genetics of primary pancreatic tumors, the biological mechanisms that enable cancer cells to spread have remained poorly understood. This is not least due to the scarcity of metastatic tissue samples and the lack of experimental models that faithfully reproduce the complex, multi-step nature of metastatic spread.
Because metastasis is responsible for the vast majority of cancer-related deaths, understanding how and when cancer cells acquire the ability to spread is of great importance for society. The goal of PACA-MET was to uncover the fundamental biological principles that determine metastatic capability in pancreatic cancer. To achieve this, the project combined large-scale genetic analyses with innovative experimental models that allow cancer evolution to be studied in living organisms.
Because metastasis is responsible for the vast majority of cancer-related deaths, understanding how and when cancer cells acquire the ability to spread is of great importance for society. The goal of PACA-MET was to uncover the fundamental biological principles that determine metastatic capability in pancreatic cancer. To achieve this, the project combined large-scale genetic analyses with innovative experimental models that allow cancer evolution to be studied in living organisms.
We developed innovative experimental tools and advanced disease models, enabling major discoveries into the mechanisms by which pancreatic cancer evolves and spreads. We identified and functionally characterized key drivers and modulators of metastasis and demonstrated that metastatic capacity is often determined very early, at the stage of the primary tumor. In most cases, metastatic tumors were genetically highly similar to their primary tumors, challenging the traditional view that metastasis develops gradually through the accumulation of late mutations. Among the identified drivers, amplification of mutated KRAS emerged as a central metastasis switch. While mutation of the KRAS gene represents the initiating event in pancreatic cancer development, we discovered that a subsequent increase in its dosage activates a program that enables cancer cells to disseminate. Crucially, we uncovered why this amplification arises so early: elevated KRAS activity is required for cellular dedifferentiation, the first step in malignant transformation. Thus, the very event that drives early tumor initiation — amplification of mutated KRAS — simultaneously equips cells with a metastatic program, providing a unifying mechanistic explanation for the early acquisition of metastatic competence in pancreatic cancer. The genetic technologies, disease models, and methods developed in PACA-MET have been widely disseminated and are now used by researchers worldwide. Their broad applicability accelerates progress across disciplines.
PACA-MET has fundamentally advanced our understanding of pancreatic cancer evolution. The project introduced a paradigm shift by demonstrating that metastatic potential is typically encoded early in tumor development, rather than arising gradually through the late accumulation of additional mutations. Moreover, it identified central molecular switches of metastasis and additional modulators that shape metastatic behavior. It also resolved a longstanding enigma by explaining why pancreatic cancer metastasizes so early, a key reason for its lethality. Beyond these biological advances, PACA-MET established unique technologies, data resources, and experimental platforms that will continue to serve as discovery engines for the international research community.