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 4

FGF19 knockdown recapitulates most phenotypes associated with HMGA1 deficiency in PDAC cell lines.

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FGF19 knockdown recapitulates most phenotypes associated with HMGA1 def...
(A) FGF19 expression in PDAC cells (E3LZ10.7, MIA PaCa-2, AsPC-1) comparing controls (empty lentiviral vector) to those with FGF19 silencing via lentiviral delivery of shRNA targeting 2 different sequences (shFGF19 1, shFGF19 2) from 3 experiments performed in triplicate. (B) Representative immunoblots (n = 3 experiments) of FGF19 protein levels in PDAC cells with and without FGF19 silencing. (C) MTT proliferation assays comparing PDAC cells with and without FGF19 silencing from 2 experiments performed in triplicate. (D) Representative images of clonogenicity assay comparing PDAC cells with and without FGF19 silencing (E3LZ10.7, MIA PaCa-2, n = 2; 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, MIA PaCa-2, n = 2; AsPC-1, n = 3). (F) Migration assay comparing PDAC cells with and without FGF19 silencing following treatment with 10 μM β-D-arabinoside (AraC) for 1 hour to mitigate effects of proliferation silencing from experiments performed in triplicate (MIA PaCa-2, n = 2; E3LZ10.7, AsPC-1, n = 3). (G) Invasion assay comparing PDAC cells with and without FGF19 silencing following treatment with 10 μM AraC for 1 hour to mitigate effects of proliferation silencing from experiments performed in triplicate (MIA PaCa-2, n = 2; E3LZ10.7, AsPC-1, n = 3). Scale bars: 200 μm. (H) Representative images (n = 3 experiments) of 3D sphere-formation assay comparing PDAC cells with and without HMGA1 silencing. (I) 3D sphere formation comparing PDAC cell lines with and without HMGA1 silencing from 3 experiments performed in triplicate. Data are presented as mean ± 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.