A widely recognized biomarker for pancreatic disease, CA19-9, thought to be benign for decades, may in fact be a promoter for the development of these diseases, including pancreatic cancer. The unexpected results were revealed using genetically engineered mice and organoid models of pancreatic disease and may suggest new avenues for the treatment of pancreatic cancer - one of the deadliest human cancers. They may also offer a lesson that can be applied to the other cancer biomarkers that have not been ascribed roles in the etiology of disease. CA19-9, a glycan carbohydrate antigen present on many proteins, is commonly expressed at low levels within the pancreas. However, patients with pancreatic diseases, including cancer, often show increased levels of the antigen within their blood. As such, it has become one of the few biomarkers for these conditions, used for more than 30 years. Even so, how CA19-9 relates to disease pathogenesis is not well known. Because mice do not express CA19-9 on their own, a mouse model useful in studying this relationship has remained elusive. Danielle Engle and colleagues developed transgenic mouse models capable of reproducing the CA19-9 levels observed in human pancreatic cancer patients and, to their surprise, found that expression of CA19-9 in these mice resulted in severe pancreatitis and hyperactivation of epidermal growth factor receptor signaling, a known driver of pancreatic cancer. While CA19-9-mediated pancreatitis could be reversed using CA19-9 antibodies, the authors also found that CA19-9-expressing transgenic mice who also harbored an oncogene developed pancreatic cancer. "By understanding whether and how CA19-9 contributes to disease, we are now poised to apply this knowledge to improve the utility of CA19-9 both as a biomarker, but also as a new treatment strategy," said Engle. In a related Perspective, Christopher Halbrook and Howard Crawford discuss the study and its implications in more detail.