HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation

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.

 

Comments:

The passage you provided highlights the role of High Mobility Group A1 (HMGA1) chromatin regulators in cancer, particularly in pancreatic ductal adenocarcinomas (PDACs). Here's a breakdown of the key points:

1. **HMGA1 in Tumors:** HMGA1 chromatin regulators are often increased in various tumors and are associated with poor outcomes. However, their specific role in cancer progression remains unclear.

2. **PDAC Characteristics:** PDACs are highly lethal tumors characterized by dense desmoplastic stroma, primarily composed of cancer-associated fibroblasts and fibrotic tissue.

3. **Epigenetic Program Involving HMGA1:** In this study, an epigenetic program is uncovered, showing that HMGA1 upregulates FGF19 during both tumor progression and the formation of stromal tissue in PDACs.

4. **Effects of HMGA1 Deficiency:** HMGA1 deficiency disrupts oncogenic properties in laboratory settings (in vitro) and impairs both the beginning and advancement of tumors in mouse models (KPC mice) and different models of PDAC.

5. **Transcriptional Networks:** RNA sequencing reveals that HMGA1 influences transcriptional networks that control cell proliferation and interactions between tumors and stroma, including the regulation of the FGF19 gene.

6. **Direct Induction of FGF19:** HMGA1 directly induces the expression of FGF19 and enhances its protein secretion by influencing active histone marks (H3K4me3, H3K27Ac).

7. **FGF19's Role:** Surprisingly, disrupting FGF19 via gene silencing or using an FGFR4 inhibitor (BLU9931) reproduces many of the effects observed with HMGA1 deficiency. This includes reducing tumor growth and the formation of desmoplastic stroma in PDAC mouse models.

8. **Clinical Relevance:** In human PDAC cases, the overexpression of both HMGA1 and FGF19 is associated with a subset of tumors having extremely poor outcomes. This suggests that HMGA1 and FGF19 could define a molecularly distinct subtype of PDAC.

In summary, the study identifies a relationship between HMGA1 and FGF19 in driving the progression of PDAC, particularly in the formation of the tumor microenvironment (desmoplastic stroma). Targeting FGF19 might offer a promising therapeutic strategy for this specific subtype of PDAC characterized by HMGA1 and FGF19 overexpression.

Related Products

Cat.No.	Product Name	Information
S7819	BLU9931	BLU9931 is a potent, selective, and irreversible FGFR4 inhibitor with IC50 of 3 nM, about 297-, 184-, and 50-fold selectivity over FGFR1/2/3, respectively.

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FGFR