Targeting tumour-promoting malignant cell-fibroblast crosstalk in pancreatic cancer

Context and Challenge
Pancreatic cancer (PDAC) is lethal for most patients, with fewer than 10% surviving more than 5 years. This is largely because the disease is diagnosed late, when it has spread to other organs, a process known as ‘metastasis’. For metastatic patients, treatments are ineffective. Additionally, PDAC is characterised by poorly understood features that promote disease progression and therapy resistance, including non-cancerous cells known as cancer-associated ‘fibroblasts’ (CAFs) that constitute most of the tumour. Our Lab’s goal is to understand how cancer cells and CAFs cooperate to drive PDAC progression, and to apply this knowledge to group patients and develop tailored therapeutics. I previously discovered that CAFs exist in two major states: myofibroblastic (myCAFs) and inflammatory (iCAFs). Over the past three years, my laboratory extended this work, systematically studying processes operating in CAFs and cancer cells, and the crosstalk between these populations. In this manner, we identified new PDAC vulnerabilities, including promotion of metastasis by a subset of myCAFs, and cancer cells’ DNA alterations-dependent signalling that shape CAF composition. These findings are beginning to unravel the complex processes that govern cancer cell-fibroblast signalling in one of the deadliest and enigmatic cancers. However, our knowledge remains largely limited to primary pancreatic tumours rather than metastases, which are the main cause of patients’ death. Therefore, we will build from our work to understand the functional heterogeneity of fibroblasts in metastatic PDAC. This knowledge is required if we are to develop better ways of diagnosing PDAC earlier and treating it more effectively.
Objectives and Aims
Our knowledge of PDAC biology is largely limited to tumours with two DNA alterations known as Kras-G12D and mutant-p53. However, my work has highlighted how additional alterations shape CAF composition, PDAC progression and therapy response....