Divergent Effects of Modulating BCAA Catabolism on Pancreatic Cancer Initiation Michael Christopher Noji

Format:

Book

Thesis/Dissertation

Author/Creator:

Noji, Michael Christopher, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

0307.

0379.

0992.

Local Subjects:

0307.

0379.

0992.

Physical Description:

1 electronic resource (166 pages)

Contained In:

Dissertations Abstracts International 87-07B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Branched-chain amino acid (BCAA) metabolism is perturbed in patients with pancreatic cancer, but the contribution of systemic or pancreas-intrinsic BCAA catabolism to pancreatic carcinogenesis remains unclear. We show here that pancreas-specific loss of DBT, the E2 subunit of the branched-chain keto-acid dehydrogenase (BCKDH) complex required for BCAA oxidation, strikingly exacerbates premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in KC (p48-Cre;KrasLSL-G12D/+) mice. However, deletion of upstream enzyme BCAT2 neither phenocopied nor rescued loss of DBT in KC mice, ruling out involvement of both upstream and downstream metabolites as mediators of PanIN promotion. Instead, we observed that DBT deficiency led to loss of the kinase BCKDK, a negative regulator of the BCKDH complex, and that, remarkably, pancreas-specific loss of BCKDK phenocopied DBT deficiency in accelerating PanIN formation. These data thus support a model in which pancreas BCKDK restrains tumorigenesis. In contrast, systemic treatment of KC mice with the BCKDK inhibitor BT2, which inhibits BCKDH phosphorylation across many tissues except the pancreas, reduced PanIN formation and preserved normal acinar area. Together the data reveal the promotion of BCAA catabolism systemically, but not within the pancreas, as a promising intervention strategy to suppress tumor initiation

Notes:

Advisors: Wellen, Kathryn; Arany, Zoltan; Feldser, David Committee members: Conn, Crystal; Stanger, Benjamin; Titchenell, Paul; Schug, Zachary

Source: Dissertations Abstracts International, Volume: 87-07, Section: B.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798276001630

Access Restriction:

Restricted for use by site license