Periodic Reporting for period 2 - PACA-MET (Genome-wide surveys and functional analysis of pancreatic cancer metastasis drivers)
Reporting period: 2021-05-01 to 2022-10-31
Pancreatic cancer is third leading cause of cancer-related death, with metastasis being the major cause of fatality. Large international efforts gave comprehensive insights into the genetics of pancreatic cancer. In contrast, equivalent studies for “metastasis genetics” were not possible, largely because of a lack of metastatic tissue resources, particularly of treatment-naive ones. Another bottleneck is the scarcity of adequate experimental models recapitulating the multi-step nature of metastasis. As a consequence, the molecular basis of metastasis remains poorly understood. We developed unique resources and tools for metastasis research and are using them to systematically interrogate the molecular underpinnings of pancreatic cancer metastasis through three major objectives: (1) We perform systematic genome-scale surveys for genes and pathways driving pancreatic cancer metastasis to different organs. We thereby characterize the genomes of our unique resource of hundreds of metastatic mouse pancreatic cancers and perform genome-wide in vivo metastasis screens using genetic tools and methods, which we developed in mice. (2) We validate newly discovered metastasis driver genes using human samples and new genetic systems and mouse metastasis models, which enable us to capture the organismal complexity of the metastatic cascade. (3) Building on our recent discovery of two prototype PDAC metastasis drivers, we perform in depth mechanistic studies to identify underlying molecular principles and vulnerabilities that could be exploited for therapeutic targeting. PACA-MET thus aims to uncover biological principles underlying of one of biggest challenges in cancer medicine.
The project already made significant contributions to the field by (i) developing cutting-edge universally applicable experimental and computational tools, experimental methods and protocols, (ii) by engineering of cell- and organismal model systems, and (iii) through fundamental new discoveries on pancreatic cancer metastasis. See more details below.
Several achievements are advancing the research field significantly beyond the state of the art:
First, we developed/improved and extensively validated new computational tools required for cancer genome analyses in mice, the model organism that is critical for PACA-MET (published in Lange et al, Nature protocols 2020; and Mueller et al Nature communications 2020). This was necessary as available pipelines had been originally developed for humans and do not account for species-specific differences in genome structures and experimental settings. These pipelines and protocols are online accessible and are now a gold-standard for mouse cancer genomics.
Second, we developed new tools and methodology for somatic genome engineering and genetic screening in the mouse pancreas (Kaltenbacher et al, Nature protocols 2022; and Braun et al, Nature protocols 2022; Weber et al Nature Reviews Cancer 2020 and unpublished). These universally applicable technologies are not only essential work-horses for the conduction of PACA-MET research, but also promise to be a major driver of scientific discoveries in the field.
Third, we engineered a series of mouse models to study newly discovered metastasis driver genes. These and other biological resources, such as our unique mouse cancer cell culture collections or the various new engineered cellular models are already being extensively requested and used locally, nationally and internationally.
Fourth, our work on metastasis biology (so far largely unpublished) has begun to give fundamental new insights in the precise molecular, cellular and organismal processes in KRAS-driven pancreatic cancer cell dissemination. We also noted that our discoveries are relevant beyond pancreatic cancer in other KRAS-initiated malignancies.
First, we developed/improved and extensively validated new computational tools required for cancer genome analyses in mice, the model organism that is critical for PACA-MET (published in Lange et al, Nature protocols 2020; and Mueller et al Nature communications 2020). This was necessary as available pipelines had been originally developed for humans and do not account for species-specific differences in genome structures and experimental settings. These pipelines and protocols are online accessible and are now a gold-standard for mouse cancer genomics.
Second, we developed new tools and methodology for somatic genome engineering and genetic screening in the mouse pancreas (Kaltenbacher et al, Nature protocols 2022; and Braun et al, Nature protocols 2022; Weber et al Nature Reviews Cancer 2020 and unpublished). These universally applicable technologies are not only essential work-horses for the conduction of PACA-MET research, but also promise to be a major driver of scientific discoveries in the field.
Third, we engineered a series of mouse models to study newly discovered metastasis driver genes. These and other biological resources, such as our unique mouse cancer cell culture collections or the various new engineered cellular models are already being extensively requested and used locally, nationally and internationally.
Fourth, our work on metastasis biology (so far largely unpublished) has begun to give fundamental new insights in the precise molecular, cellular and organismal processes in KRAS-driven pancreatic cancer cell dissemination. We also noted that our discoveries are relevant beyond pancreatic cancer in other KRAS-initiated malignancies.