408 Requirement for Ikkβ in a Mouse Model of Pancreatic Ductal Adenocarcinoma

ABSTRACTPancreatic cancer (PC) is acquired postnatally; to mimic this scenario, we developed an inducible KrasG12D; Ptf1a-CreER™ (iKC) mouse model, in which Kras is activated postnatally at week 16 upon tamoxifen (TAM) administration. Upon TAM treatment, iKC mice develop pancreatic intraepithelial neoplasia (PanIN) lesions and PC with metastasis at the fourth and fortieth weeks, respectively, and exhibited acinar-to-ductal metaplasia (ADM) and transdifferentiation. Kras activation upregulated the transcription factors Ncoa3, p-cJun and FoxM1, which in turn upregulated expression of transmembrane mucins (Muc1, Muc4 and Muc16) and secretory mucin (Muc5Ac). Interestingly, knockdown of KrasG12D in multiple PC cell lines resulted in downregulation of MUC1, MUC4, MUC5AC and MUC16. In addition, iKC mice exhibited ADM and transdifferentiation. Our results show that the iKC mouse more closely mimics human PC development and can be used to investigate pancreatic ductal adenocarcinoma (PDAC) biomarkers, early onset of PDAC, and ADM. The iKC model can also be used for preclinical strategies such as targeting mucin axis alone or in combination with neo-adjuvant, immunotherapeutic approaches and to monitor chemotherapy response.

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Hes1 Controls Exocrine Cell Plasticity and Restricts Development of Pancreatic Ductal Adenocarcinoma in a Mouse Model

American Journal Of Pathology ◽

10.1016/j.ajpath.2016.07.025 ◽

2016 ◽

Vol 186 (11) ◽

pp. 2934-2944 ◽

Cited By ~ 11

Author(s):

Ana Hidalgo-Sastre ◽

Roxanne L. Brodylo ◽

Clara Lubeseder-Martellato ◽

Bence Sipos ◽

Katja Steiger ◽

...

Keyword(s):

Mouse Model ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Cell Plasticity ◽

Exocrine Cell

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MicroRNA-21 Is Induced Early in Pancreatic Ductal Adenocarcinoma Precursor Lesions

Clinical Chemistry ◽

10.1373/clinchem.2009.137364 ◽

2010 ◽

Vol 56 (4) ◽

pp. 603-612 ◽

Cited By ~ 142

Author(s):

Maël Chalret du Rieu ◽

Jérôme Torrisani ◽

Janick Selves ◽

Talal Al Saati ◽

Anny Souque ◽

...

Keyword(s):

Early Detection ◽

Mouse Model ◽

Pancreatic Ductal Adenocarcinoma ◽

Early Stage ◽

Survival Rates ◽

Ductal Adenocarcinoma ◽

Early Event ◽

Precursor Lesions ◽

Tissue Samples ◽

Ductal Cells

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has the poorest overall prognosis among gastrointestinal cancers; however, curative resection in early-stage PDAC greatly improves survival rates, indicating the importance of early detection. Because abnormal microRNA production is commonly detected in cancer, we investigated noninvasive precursor pancreatic intraepithelial neoplasia (PanIN) lesions for microRNA production as a potential early biomarker of PDAC. Methods: Pathologists identified and classified ductal lesions. We extracted total RNA from laser-capture microdissected PanIN tissue samples from a conditional KRAS(G12D) mouse model (n = 29) or of human origin (n = 38) (KRAS is v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). MicroRNA production was quantified by quantitative real-time PCR. Internal controls included 5S and U6 RNAs. Results: Production of microRNAs miR-21, miR-205, and miR-200 paralleled PanIN progression in the KRAS(G12D) mouse model, compared with microRNA production in samples of nonpathologic ducts. miR-21 demonstrated the highest relative concentrations in the precursor lesions. Interestingly, miR-205 and miR-21 up-regulation preceded phenotypic changes in the ducts. The production of microRNAs miR-21, miR-221, miR-222, and let-7a increased with human PanIN grade, with peak production occurring in hyperplastic PanIN-2/3 lesions. In situ hybridization analysis indicated miR-21 production to be concentrated in pathologic ductal cells. miR-21 production was regulated by KRAS(G12D) and epidermal growth factor receptor in PDAC-derived cell lines. Conclusions: Aberrant microRNA production is an early event in the development of PanIN. Our findings indicate that miR-21 warrants further investigation as a marker for early detection of PDAC.

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