Abstract
SummaryThe exocrine pancreas, consisting of ducts and acini, is the site of origin of pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Our understanding of the genesis and progression of human pancreatic diseases, including PDAC, is limited because of challenges in maintaining human acinar and ductal cells in culture. Here we report induction of human pluripotent stem cells toward pancreatic ductal and acinar organoids that recapitulate properties of the neonatal exocrine pancreas. Expression of the PDAC-associated oncogene GNASR201C induces cystic growth more effectively in ductal than acinar organoids, whereas KRASG12D is more effective in modeling cancer in vivo when expressed in acinar compared with ductal organoids. KRASG12D, but not GNASR201C, induces acinar-to-ductal metaplasia-like changes in culture and in vivo. We develop a renewable source of ductal and acinar organoids for modeling exocrine development and diseases and demonstrate lineage tropism and plasticity for oncogene action in the human pancreas.
Highlights
The pancreas is composed of endocrine and exocrine compartments
Precursor lesions of pancreatic cancer can be classified into four main subtypes based on their clinical pathology: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMNs), intratubular papillary neoplasms (ITPNs), and mucinous neoplasms (MCNs) (Cooper et al, 2013; Hruban et al, 2000, 2007)
To design the culture media, we focused on pathways with established roles in exocrine pancreas specification
Summary
The pancreas is composed of endocrine and exocrine compartments. the endocrine pancreas harbors islets of Langerhans, the exocrine pancreas, which makes up over 90% of the total pancreas volume, contains the ductal (~5%) and acinar (~85%) epithelia. Mutation in GNAS involving codon 201 is observed frequently in IPMN lesions, either by itself or in combination with mutant KRAS (Amato et al, 2014; Fukayama et al., 1986; Wu et al, 2011), and adjacent invasive PDAC, identifying GNAS as a driver in IPMN-derived PDAC. It is unclear how different precancerous lesions affect PDAC development and how the cellular origins of PDAC affect development of precancerous lesions and clinical prognosis
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