A new technique to study tissue samples in 3D has revealed that pancreatic cancers can start and grow in two distinct ways, solving a decades-old mystery of how tumors form. The new method published in Nature could help researchers to get more information from tissue biopsies and may lead to improved treatments for pancreatic cancers.

The pancreas is a crucial organ that sits behind our stomach and plays a key role in digestion. It relies on a network of ducts linking it to other digestive organs, and the most common pancreatic cancers are found in the ducts. However, until now it has only been possible to see 2D slices of these ductal cancers, which contained an unexplained variety of abnormal shapes.

"To investigate the origins of pancreatic cancer, we spent six years developing a new method to analyse cancer biopsies in three dimensions," explains co-lead author of the research paper. "This technique revealed that cancers develop in the duct walls and either grow inwards or outwards depending on the size of the duct. This explains the mysterious shape differences that we've been seeing in 2D slices for decades."

By analysing developing cancers in 3D, the team defined two distinct types of cancer formation originating from ductal cells: 'endophytic' tumors which grow into the ducts and 'exophytic' tumors which grow outwards. To find out what makes cancer cells grow in a particular way, they analysed detailed 3D images and worked with biophysicists who created sophisticated computer models.

Myosin activity was higher apically than basally in wild-type cells, but upon transformation this gradient was lost in both lesion types. Three-dimensional vertex model simulations and a continuum theory of epithelial mechanics, which incorporate the cytoskeletal changes observed in transformed cells, indicated that the diameter of the source epithelium instructs the morphology of growing tumors. Three-dimensional imaging revealed that—consistent with theory predictions—small pancreatic ducts produced exophytic growth, whereas large ducts deformed endophytically. 

"We made a simulation of the ducts, describing individual cell geometry to understand tissue shape," explains the other co-lead author of the paper. "The model and experimental results both confirmed that cancer grew outwards when the diameter of the duct was less than approximately twenty micrometres, around a fiftieth of a millimetre."

The team also applied the technique to other organs, and found that cancers in the airways of the lungs and ducts in the liver behave in the same way. This shows that the mechanism the teams discovered is not specific to the pancreas and also applies to other cancers.

"Both the data and our models indicate that the two different mechanisms of tumour growth are purely down to the innate physics of the system," explains the author. "Like most cancers, ductal pancreatic cancer starts with a single defective cell that starts dividing. We found that very quickly, when there are only a few cells, the tumor has already started to grow either inwards or outwards depending on duct diameter. Defining this fundamental process will help us to better understand how cancer grows in many places across the body."

https://www.crick.ac.uk/news/2019-01-30_new-3d-imaging-technique-reveals-how-pancreatic-cancers-start

https://www.nature.com/articles/s41586-019-0891-2