Three-dimensional analysis of the patterns of growth and mechanisms of evading therapy of pancreatic cancer in whole organs and thick slabs of tissue using active and passive SHANEL technology

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Pancreatic cancer is one of the most deadly cancers of all. In order to improve the treatment of pancreatic cancer, research must be based on the latest available methods. This is the only way to improve the prognosis of affected patients in the long term. In the present application, the three-dimensional growth pattern of pancreatic cancer is to be investigated using a novel microscopic method called SHANEL. SHANEL stands for "small-micelle-mediated human organ efficient clearing and labelling". In contrast to earlier methods, SHANEL is used to examine whole tumours in one piece. This has the advantage that several regions of the tumour can be analysed simultaneously. In this way, the relationship of the tumor cells to their microenvironment can be assessed. For the first time, it is now possible to examine parts of the tumour that grow into vessels and lead to metastases. In addition, mechanisms underlying the clinically frequently observed resistance to chemotherapy can be investigated.The proposed investigations are planned in the group of Dr. Wood and Dr. Hruban at Johns-Hopkins University, who have already carried out three-dimensional microscopic analyses of smaller tumor parts. With the help of the existing expertise of this group, the SHANEL investigation will now be extended to pancreatic cancer.The research project is therefore based on three main objectives. In the first step, the SHANEL technology will be adapted to the special requirements of the very hard and connective tissue-rich pancreatic cancer. The second main goal is the analysis of the 3D growth of human pancreatic cancer cells in tissue in relation to other structures such as nerves, vessels and pancreatic ducts. The main focus is to evaluate whether there is a directed, non-random growth versus an undirected, random growth. Background are observations of the group around Dr. Wood and Dr. Hruban, which assume a directed growth. The third main objective is to investigate the morphological changes in pancreatic carcinomas that have undergone neoadjuvant chemotherapy, i.e. chemotherapy that precedes surgery. Three-dimensional microscopy of pancreatic carcinomas treated with neoadjuvant chemotherapy will show where the surviving cancer cells are located. It will be investigated whether there are anatomical niches that protect tumour cells. Recent data from the group suggest that cancer cells that have invaded the normal pancreatic duct system respond less well to chemotherapy than those located in the stroma.In summary, the present research project proposes to identify mechanisms of metastasis and resistance to therapy by high-resolution three-dimensional microscopy of whole pancreatic tumors. The results could improve the understanding of pancreatic carcinoma in the long term.