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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.

A 51-year-old woman suffered cardiac arrest requiring emergent intraosseous access that abutted the tibial component of her total knee arthroplasty. She developed a wound at the site and knee pain which was concerning for deep infection. Subsequent imaging was consistent with osteonecrosis developing around the tibial component. The component eventually loosened, requiring a revision surgery. Her deep cultures remained negative throughout. Her findings are most consistent with osteonecrosis and aseptic loosening of her prosthesis. While intraosseous access may be beneficial during resuscitation, it has complications. This is the first reported case of osteonecrosis secondary to intraosseous access leading to prosthetic loosening necessitating a revision surgery.

The function of high mobility group A1 (Hmga1) chromatin remodelling proteins in intestinal stem cells (ISC) is unknown. Here, the authors show that Hmga1 amplifies Wnt/β-catenin signalling to enhance self-renewal and inducesSox9to expand the Paneth cell compartment and enrich the ISC niche.