HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation
Lionel Chia, … , Laura Wood, Linda Resar
Lionel Chia, … , Laura Wood, Linda Resar
Published March 15, 2023
Citation Information: J Clin Invest. 2023;133(6):e151601. https://doi.org/10.1172/JCI151601.
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Research Article Oncology

HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation

Abstract

High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.

Authors

Lionel Chia, Bowen Wang, Jung-Hyun Kim, Li Z. Luo, Shuai Shuai, Iliana Herrera, Sophia Y. Chen, Liping Li, Lingling Xian, Tait Huso, Mohammad Heydarian, Karen Reddy, Woo Jung Sung, Shun Ishiyama, Gongbo Guo, Elizabeth Jaffee, Lei Zheng, Leslie M. Cope, Kathy Gabrielson, Laura Wood, Linda Resar

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Figure 1

HMGA1 knockdown disrupts oncogenic properties in PDAC cell lines.

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HMGA1 knockdown disrupts oncogenic properties in PDAC cell lines. (A) H...
(A) HMGA1 expression in PDAC cell lines (E3LZ10.7, MIA PaCa-2, AsPC-1) comparing controls (transduced with empty lentiviral vector) to HMGA1 silencing via lentiviral delivery of shRNA targeting 2 different sequences (shHMGA1 1, shHMGA1 2) from 3 experiments performed in triplicate. (B) Representative immunoblots (n = 3 experiments) of HMGA1 in PDAC cells with and without HMGA1 silencing. (C) Proliferation (by MTT) comparing PDAC cells with and without HMGA1 silencing from 3 experiments performed in triplicate. (D) Representative images of soft agar clonogenicity assay in PDAC cells with and without HMGA1 silencing (E3LZ10.7, n = 2; MIA PaCa-2 and AsPC-1, n = 3). Scale bars: 200 μm. (E) Clonogenic efficiency comparing PDAC cell lines with and without HMGA1 silencing from experiments performed in triplicate (E3LZ10.7, n = 2; MIA PaCa-2 and AsPC-1, n = 3). (F) Migration comparing PDAC cells with and without HMGA1 silencing following treatment with 10 μM cytosine β-D-arabinoside (AraC) for 1 hour to mitigate effects of proliferation from experiments performed in triplicate (E3LZ10.7 and MIA PaCa-2, n = 2; AsPC-1, n = 3). (G) Invasion comparing PDAC cells with and without HMGA1 silencing following treatment with 10 μM AraC for 1 hour to mitigate effects of proliferation from experiments performed in triplicate (MIA PaCa-2, n = 2; E3LZ10.7 and AsPC-1, n = 3). (H) Representative images (n = 3 experiments) of 3D sphere formation in PDAC cell lines with and without HMGA1 silencing. Scale bars: 200 μm. (I) 3D sphere formation comparing PDAC cell lines with and without HMGA1 silencing from 3 experiments performed in triplicate. Data are presented as mean ± standard deviation (SD). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by 1-way ANOVA with Dunnett’s multiple-comparison test (A, C, E–G, and I). Scale bars: 200 μm.