https://home.ccr.cancer.gov/ncifdaproteomics/pdf/CancerCell-PanIN.pdf

Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse

Organoid Models of Human and Mouse Ductal Pancreatic Cancer

With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival.

/pdf/genetics-and-biology-of-pancreatic-ductal-adenocarcinoma-2k15657c9p.pdf

Genetics and biology of pancreatic ductal adenocarcinoma

https://www.cell.com/cancer-cell/pdf/S1535-6108(07)00027-X.pdf

Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.

microRNAs are functional, 22 nt, noncoding RNAs that negatively regulate gene expression. Disturbance of microRNA expression may play a role in the initiation and progression of certain diseases. A microRNA expression signature has been identified that is associated with pancreatic cancer. This has been accomplished with the application of real-time PCR profiling of over 200 microRNA precursors on specimens of human pancreatic adenocarcinoma, paired benign tissue, normal pancreas, chronic pancreatitis and nine pancreatic cancer cell lines. Hierarchical clustering was able to distinguish tumor from normal pancreas, pancreatitis and cell lines. The PAM algorithm correctly classified 28 of 28 tumors, 6 of 6 normal pancreas and 11 of 15 adjacent benign tissues. One hundred microRNA precursors were aberrantly expressed in pancreatic cancer or desmoplasia (p < 0.01), including microRNAs previously reported as differentially expressed in other human cancers (miR-155, miR-21, miR-221 and miR-222) as well as those not previously reported in cancer (miR-376a and miR-301). Most of the top aberrantly expressed miRNAs displayed increased expression in the tumor. Expression of the active, mature microRNA was validated using a real-time PCR assay to quantify the mature microRNA and Northern blotting. Reverse transcription in situ PCR showed that three of the top differentially expressed miRNAs (miR-221, -376a and -301) were localized to tumor cells and not to stroma or normal acini or ducts. Aberrant microRNA expression may offer new clues to pancreatic tumorigenesis and may provide diagnostic biomarkers for pancreatic adenocarcinoma.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.22394

Expression profiling identifies microRNA signature in pancreatic cancer

https://www.cell.com/cancer-cell/pdf/S1535-6108(03)00140-5.pdf

Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis

Epithelial metaplasia occurs when one predominant cell type in a tissue is replaced by another, and is frequently associated with an increased risk of subsequent neoplasia. In both mouse and human pancreas, acinar-to-ductal metaplasia has been implicated in the generation of cancer precursors. We show that pancreatic epithelial explants undergo spontaneous acinar-to-ductal metaplasia in response to EGFR signaling, and that this change in epithelial character is associated with the appearance of nestin-positive transitional cells. Lineage tracing involving Cre/lox-mediated genetic cell labeling reveals that acinar-to-ductal metaplasia represents a true transdifferentiation event, mediated by initial dedifferentiation of mature exocrine cells to generate a population of nestin-positive precursors, similar to those observed during early pancreatic development. These results demonstrate that a latent precursor potential resides within mature exocrine cells, and that this potential is regulated by EGF receptor signaling. In addition, these observations provide a novel example of rigorously documented transdifferentiation within mature mammalian epithelium, and suggest that plasticity of mature cell types may play a role in the generation of neoplastic precursors.

Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates

The developmental plasticity of adult pancreas is evidenced by the ability to undergo conversion between different epithelial cell types Specific examples of such conversions include acinar to ductal metaplasia, ductal to islet metaplasia, and generation of ductal structures within islets Although 90% of human pancreatic cancers are classified as ductal adenocarcinoma, markers of all pancreatic epithelial cell types (acini, ductal, and endocrine) as well as markers of gastric and intestinal lineages can be detected in these tumors In recent years considerable knowledge has been gained regarding regulation of cellular differentiation and various signaling pathways involved in normal and neoplastic pancreas through studies of pancreatic cancer and immortalized ductal cell lines However, these studies provide little insight into the context of normal developmental cues, the disruption of which leads to organ pathology Here we have described a detailed method for preparation, maintenance, and manipulation of adult and embryonic mouse pancreas These methods may be utilized in studies involving normal epithelial differentiation, contributing to improved understanding of pancreatic development and disease

/pdf/primary-explant-cultures-of-adult-and-embryonic-pancreas-13c4d87j92.pdf

Yoshiharu Miyamoto

Papers

Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis

Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates

Primary explant cultures of adult and embryonic pancreas.