Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells

Abstract

Development of systems that reconstitute hallmark features of human pancreatic intraepithelial neoplasia (PanINs), the precursor to pancreatic ductal adenocarcinoma, could generate new strategies for early diagnosis and intervention. However, human cell-based PanIN models with defined mutations are unavailable. Here, we report that genetic modification of primary human pancreatic cells leads to development of lesions resembling native human PanINs. Primary human pancreas duct cells harbouring oncogenic KRAS and induced mutations in CDKN2A, SMAD4 and TP53 expand in vitro as epithelial spheres. After pancreatic transplantation, mutant clones form lesions histologically similar to native PanINs, including prominent stromal responses. Gene expression profiling reveals molecular similarities of mutant clones with native PanINs, and identifies potential PanIN biomarker candidates including Neuromedin U, a circulating peptide hormone. Prospective reconstitution of human PanIN development from primary cells provides experimental opportunities to investigate pancreas cancer development, progression and early-stage detection.

Modeling Human Digestive Diseases With CRISPR-Cas9–Modified Organoids

“…As a strategy to genetically replicate the pathogenesis of human PDAC, 2 studies recently adopted CRISPR/Cas9mediated genome editing and modified PDAC driver genes in human pancreatic ductal organoids. 41,121 Lee et al 121 transduced KRAS G12V and ERBB2 (hereafter K and E, respectively) and inactivated TP53, CDKN2A, and SMAD4 (hereafter T, C, and S, respectively) by lentiviral delivery of CRISPR-Cas9. Although non-transformed or K ductal organoids ceased proliferation after several passages, KCTS and KCTSE ductal organoids propagated exponentially at least for 4 months, indicating the immortalization of pancreatic ductal cells by multiple cancer pathway mutations.…”

Effect of neuromedin�U on allergic airway inflammation in an asthma model (Review)

“…Neuromedin U (NMU) is a multifunctional neuropeptide with pleiotropic effects, including the mediation of intestinal peristalsis and the modulation of the sense of satiety, body weight, circadian oscillation, bone formation, insulin production, cancer development, energy balance and metabolism (8)(9)(10)(11)(12). However, these effects will not be addressed in the present review.…”

Dendron‐Grafted Polylysine‐Based Dual‐Modal Nanoprobe for Ultra‐Early Diagnosis of Pancreatic Precancerosis via Targeting a Urokinase‐Type Plasminogen Activator Receptor

“…Pancreatic ductal adenocarcinoma (PDAC), with 5‐year survival rate of 6% and an increasing incidence, is on track to become the second most common cause of cancer‐related death by 2030 . PDAC is believed to be developed from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs) that undergo a series of architectural, cytologic, and genetic changes . Despite research efforts over the past 50 years, the conventional treatment approaches such as surgery, radiation, chemotherapy, or combinations of these treatments have little efficacy on development of aggressive neoplasm.…”