scholarly journals Metformin Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-induced Obesity in the Conditional KrasG12D Mouse Model

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Hui-Hua Chang ◽  
Aune Moro ◽  
Caroline Ei Ne Chou ◽  
David W. Dawson ◽  
Samuel French ◽  
...  
Keyword(s):  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Diet Induced Obesity

scholarly journals Metformin alters the duodenal microbiome and decreases the incidence of pancreatic ductal adenocarcinoma promoted by diet-induced obesity

2019 ◽  
Vol 317 (6) ◽  
pp. G763-G772 ◽  
Author(s):  
Tien S. Dong ◽  
Hui-Hua Chang ◽  
Meg Hauer ◽  
Venu Lagishetty ◽  
William Katzka ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Microbial Composition ◽  
Diet Induced Obesity ◽  
Potential Mediator

Pancreatic ductal adenocarcinoma (PDAC)’s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. In previous work, we have shown that metformin can prevent the increased incidence of PDAC in a KrasG12D mouse model subjected to a diet high in fat and calories (HFCD). One potential way that metformin can affect the host is through alterations in the gut microbiome. Therefore, we investigated microbial associations with PDAC development and metformin use in the same mouse model. Lox-Stop-Lox Kras G12D/+ (LSL-Kras G12D/+); p48-Cre (KC) mice were given control diet, HFCD, or HFCD with 5 mg/mL metformin in drinking water for 3 mo. At the end of the 3 mo, 16S rRNA sequencing was performed to characterize microbiome composition of duodenal mucosal, duodenal luminal, and cecal luminal samples. KC mice on an HFCD demonstrated depletion of intact acini and formation of advanced pancreatic intraepithelial neoplasia. This effect was completely abrogated by metformin treatment. HFCD was associated with significant changes in microbial composition and diversity in the duodenal mucosa and lumen, much of which was prevented by metformin. In particular, Clostridium sensu stricto was negatively correlated with percent intact acini and seemed to be inhibited by the addition of metformin while on an HFCD. Administration of metformin eliminated PDAC formation in KC mice. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin. NEW & NOTEWORTHY Pancreatic ductal adenocarcinoma (PDAC)’s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. Administration of metformin eliminated PDAC formation in KC mice with diet-induced obesity. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.

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

2010 ◽  
Vol 138 (5) ◽  
pp. S-61
Author(s):  
Shin Maeda ◽  
Yohko Hikiba ◽  
Kei Sakamoto ◽  
Hayato Nakagawa ◽  
Yoshihiro Hirata ◽  
...  
Keyword(s):  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma

Abstract 1565: β-hydroxy-β-methylbutyrate enhances anti-PD1 immunotherapy in a mouse model of pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Suhas K. Etigunta ◽  
Michael F. Coleman ◽  
Alex J. Pfeil ◽  
Laura M. Lashinger ◽  
Zhengrong Cui ◽  
...  
Keyword(s):  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma

Mo1988 - Metformin Prevents Kras-Mutant Pancreatic Ductal Adenocarcinoma Promoted by Diet-Induced Obesity

2018 ◽  
Vol 154 (6) ◽  
pp. S-873
Author(s):  
Hui-Hua Chang ◽  
James Sinnett-Smith ◽  
Andrea I. Schmidt ◽  
Oscar J. Hines ◽  
Guido Eibl ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Diet Induced Obesity

Abstract 2384: A novel mouse model for the study of c-MYC during initiation and progression of pancreatic ductal adenocarcinoma

2011 ◽  
Author(s):  
Wan-Chi Lin ◽  
Qian Zhang ◽  
Rene Opavsky ◽  
Dominick J. DiMaio ◽  
Dean W. Felsher ◽  
...  
Keyword(s):  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma

scholarly journals Acinar transformed ductal cells exhibit differential mucin expression in a tamoxifen-induced pancreatic ductal adenocarcinoma mouse model

Biology Open ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. bio052878
Author(s):  
Kavita Mallya ◽  
Dhanya Haridas ◽  
Parthasarathy Seshacharyulu ◽  
Ramesh Pothuraju ◽  
Wade M. Junker ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Response ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Ductal Cells ◽  
Mucin Expression ◽  
Acinar To Ductal Metaplasia

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.

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

2016 ◽  
Vol 186 (11) ◽  
pp. 2934-2944 ◽  
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

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

2010 ◽  
Vol 56 (4) ◽  
pp. 603-612 ◽  
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.

A mouse model for pain and neuroplastic changes associated with pancreatic ductal adenocarcinoma

Pain ◽  
2017 ◽  
Vol 158 (8) ◽  
pp. 1609-1621 ◽  
Author(s):  
Deepitha Selvaraj ◽  
Michael Hirth ◽  
Jagadeesh Gandla ◽  
Rohini Kuner
Keyword(s):  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma
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