Periodic Reporting for period 1 - NERVASION (Targeting microenvironment of cancer-invaded-nerves in pancreatic adenocarcinoma.)
Reporting period: 2021-06-01 to 2023-05-31
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumour with a poor prognosis, a high mortality rate, and no effective therapies. One of the pathological hallmarks of PDAC is the infiltration of cancer cells along nerves and within nerve fibres. Nerve invasion is present in many solid tumours, but its prevalence is highest in PDAC, ranging between 70% and 98%. It occurs early during PDAC development and is associated with increased tumour recurrence, enhanced metastasis, decreased overall survival, and a highly pro-tumorigenic immune microenvironment. The cellular and molecular mechanisms acting within cancer-invaded nerves to promote tumorigenesis remain unknown, precluding novel therapeutics development. In this project, we applied cutting-edge technologies to human pancreatic adenocarcinoma tissues and profiled the microenvironment of cancer-invaded nerves. We identified cellular and molecular players acting within cancer-invaded nerves, and the functional role of identified factors in cancer proliferation and invasiveness will soon be tested with in vitro and in vivo assays. In the long term, the results of the project might identify novel therapeutic targets for PDAC.
Within the scope of the action, the researcher introduced mouse models of pancreatic adenocarcinoma to the laboratory and characterized them in regard to the extent and kinetics of perineural invasion. According to previous research, we expected to find instances of perineural invasion in both orthotopic (Jurcak et al. 2019, Gastroenterology) and spontaneous mouse models (Renz et al. 2018, Cancer Cell; Na'ara et al. 2018, Oncogene). Surprisingly, after careful examination of various mouse models we could not detect the typical invasion of cancer cells into nerve trunks as observed in human pancreatic adenocarcinoma patients. Thus, we concluded that mouse models reflect poorly the human perineural invasion. Indeed, recent scientific literature provides data that support our findings (Saricaoglu et al. 2020, Neurogastroenterology & Motility; Jiang et al. 2022, Cancer Letters). Thus, the researcher gained important knowledge about pancreatic adenocarcinoma mouse models, which will be invaluable during the researcher's future research. In addition, this knowledge will be disseminated on the project website. Importantly, the mouse model of pancreatic adenocarcinoma has been used by the researcher to pursue other scientific questions and optimize and introduce protocols for studying pancreas tissue at the transcriptional level.
Within the scope of the action, the researcher obtained FFPE tissue blocks from three human pancreatic adenocarcinoma patients that contained either cancer-invaded nerves or control/uninvaded nerves. The specimens were stained with hematoxylin and eosin, and processed for 10xgenomics CytAssist Visium spatial transcriptomic. The data are of good quality and preliminary analysis on samples coming from one patient identified genes that operate specifically within cancer-invaded nerves. In close future, we will expand the analysis to samples from other patients, confirm major findings using multiplexed immunohistochemistry, and address the functional role of identified factors in driving cancer proliferation or cancer invasiveness with in vitro and in vivo assays. Thus, within the scope of the action, the researcher generated a dataset that will be used to identify gemes operating within cancer-invaded nerves and subsequently experimentally address their functional importance for cancer proliferation and invasiveness. The results will be a basis for the master thesis project of the student and will ultimately be published in the form of scientific publication. Furthermore, the dataset will be used for other scientific projects running in the lab.
Within the scope of the action, the researcher obtained FFPE tissue blocks from three human pancreatic adenocarcinoma patients that contained either cancer-invaded nerves or control/uninvaded nerves. The specimens were stained with hematoxylin and eosin, and processed for 10xgenomics CytAssist Visium spatial transcriptomic. The data are of good quality and preliminary analysis on samples coming from one patient identified genes that operate specifically within cancer-invaded nerves. In close future, we will expand the analysis to samples from other patients, confirm major findings using multiplexed immunohistochemistry, and address the functional role of identified factors in driving cancer proliferation or cancer invasiveness with in vitro and in vivo assays. Thus, within the scope of the action, the researcher generated a dataset that will be used to identify gemes operating within cancer-invaded nerves and subsequently experimentally address their functional importance for cancer proliferation and invasiveness. The results will be a basis for the master thesis project of the student and will ultimately be published in the form of scientific publication. Furthermore, the dataset will be used for other scientific projects running in the lab.
The project generated the first spatial transcriptomic dataset of invaded and non-invaded nerves in human pancreatic adenocarcinoma specimens. The dataset will be used to identify molecular signals acting within cancer-invaded nerves. Subsequent in vitro studies will address the functional role of identified factors in driving cancer proliferation or invasiveness. In the long term, the results of the action might guide biomarker design, help in patient stratification, or reveal therapeutic vulnerabilities of cancer cells. In the short term, data generated within the project's scope will be critical for 1) other group members within the laboratory, e.g. PhD students will use data to identify conserved receptor-ligand interactions across different cancer types, and 2) the scientific community when disseminated in the form of publication. Furthermore, protocols, methods, and approaches tested within the project's scope are innovative and will be shared with the scientific community on the project website and in future publications.