Abstract
Lumens are crucial features of the tissue architecture in both the healthy exocrine pancreas, where ducts shuttle enzymes from the acini to the intestine, and in the precancerous lesions of the highly lethal pancreatic ductal adenocarcinoma (PDAC), similarly displaying lumens that can further develop into cyst-like structures. Branched pancreatic-cancer derived organoids capture key architectural features of both the healthy and diseased pancreas, including lumens. However, their transition from a solid mass of cells to a hollow tissue remains insufficiently explored. Here, we show that organoids display two orthogonal but complementary lumen formation mechanisms: one relying on fluid intake for multiple microlumen nucleation, swelling and fusion, and the other involving the death of a central cell population, thereby hollowing out cavities. These results shed further light on the processes of luminogenesis, deepening our understanding of the early formation of PDAC precancerous lesions, including cystic neoplasia.