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 12

FGFR4 inhibition with BLU9931 decreases tumorigenesis and stroma formation in human PDAC orthotopic implants.

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FGFR4 inhibition with BLU9931 decreases tumorigenesis and stroma formati...
(A) Tumors (top) and volume comparisons (bottom) from orthotopic implantation of E3LZ10.7 cells in mice treated with BLU9931 or vehicle control. Data presented as mean ± SEM. (B) Representative images (n = 10 per condition) of tumors stained with H&E (top row) and for HMGA1 (second row), FGF19 (third row), fibrosis (trichrome; fourth row), and Ki-67 (bottom row) in E3LZ10.7 orthotopic implants of mice treated with BLU9931 or vehicle. (C) Comparison of stromal fibrosis scores in E3LZ10.7 orthotopic implants based on a 3-point system. (D) Comparison of Ki-67+ cells in E3LZ10.7 orthotopic implants of mice treated with BLU9931 or with vehicle control. (E) Representative IF images of CAFs in E3LZ10.7 orthotopic implants of mice treated with BLU9931 or with vehicle. (F) Comparison of CAFs in E3LZ10.7 orthotopic implants of mice treated with BLU9931 or vehicle. Total CAF number ascertained by costaining with DAPI and for PDPN; α-SMA, CD74, and IL-6 were used to identify percentage of total CAFs positive for each marker. Data in C–D were based on 10 fields from 3 different mice/group at x20 magnification (n = 10/condition); data in E were based on 10 fields from 1 mouse/group at x20 magnification (n = 10/condition). Data presented as mean ± SD (C, D, and F). Significance was evaluated by Mann-Whitney test (A, C, and D) or 2-tailed Student’s t test for α-SMA+ and CD74+ CAFs (data normally distributed) and Mann-Whitney for IL-6+ CAFs (data not normally distributed) (F). **P < 0.01, ****P < 0.0001. Scale bars: 200 μm.