Heterocellular crosstalk and architecture of the pancreatic tumour microenvironment

A fibroinflammatory microenvironment coevolves with many tumour types and profoundly influences disease progression and response to therapy. Pancreatic cancer is the archetype of a fibroinflammatory tumour, with non-malignant stromal elements comprising the volumetric majority of the tumour tissue. A convergence of three factors - technological advances enabling deep understanding of heterocellular crosstalk in these complex tumours; therapeutic advances revealing meaningful vulnerabilities in this notoriously chemoresistant, immunosuppressive disease; and conceptual advances towards distilling the conserved features and key functions of stromal elements amid this complexity - has positioned the field in a promising era for discovery, wherein our ever-improving understanding of the pancreatic tumour microenvironment is poised for translational impact. Emerging pan-cancer analyses highlight features of tumour microenvironments conserved not only among pancreatic cancer specimens but also across anatomic sites, such that lessons learnt about the organization of tumour tissue architecture and the role of oncogenic KRAS signalling in this process in other tumours have shaped our understanding of heterocellular dependencies in pancreatic cancer and vice versa. Here, we review recent developments sculpting our current understanding of the diverse features of the pancreatic tumour microenvironment and emerging means to leverage these developments for the benefit of patients with pancreatic cancer.