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

Kavita Mallya; Dhanya Haridas; Parthasarathy Seshacharyulu; Ramesh Pothuraju; Wade M. Junker; Shiv Ram Krishn; Sakthivel Muniyan; Raghupathy Vengoji; Surinder K. Batra; Satyanarayana Rachagani

doi:10.1242/bio.052878

Biology Open (Sep 2020)

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

Kavita Mallya,
Dhanya Haridas,
Parthasarathy Seshacharyulu,
Ramesh Pothuraju,
Wade M. Junker,
Shiv Ram Krishn,
Sakthivel Muniyan,
Raghupathy Vengoji,
Surinder K. Batra,
Satyanarayana Rachagani

Affiliations

Kavita Mallya: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Dhanya Haridas: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Parthasarathy Seshacharyulu: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Ramesh Pothuraju: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Wade M. Junker: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Shiv Ram Krishn: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Sakthivel Muniyan: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Raghupathy Vengoji: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Surinder K. Batra: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Satyanarayana Rachagani: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA

DOI: https://doi.org/10.1242/bio.052878
Journal volume & issue: Vol. 9, no. 9

Abstract

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Pancreatic 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.

Published in Biology Open

ISSN: 2046-6390 (Online)
Publisher: The Company of Biologists
Country of publisher: United Kingdom
LCC subjects: Science: Biology (General)
Website: https://journals.biologists.com/bio

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