Elevated fibroblast growth factor‐inducible 14 expression transforms proneural‐like gliomas into more aggressive and lethal brain cancer

Abstract

High‐grade gliomas (HGGs) are aggressive, treatment‐resistant, and often fatal human brain cancers. The TNF‐like weak inducer of apoptosis (TWEAK)/fibroblast growth factor‐inducible 14 (Fn14) signaling axis is involved in tissue repair after injury and constitutive signaling has been implicated in the pathogenesis of numerous solid cancers. The Fn14 gene is expressed at low levels in the normal, uninjured brain but is highly expressed in primary isocitrate dehydrogenase wild‐type and recurrent HGGs. Fn14 signaling is implicated in numerous aspects of glioma biology including brain invasion and chemotherapy resistance, but whether Fn14 overexpression can directly promote tumor malignancy has not been reported. Here, we used the replication‐competent avian sarcoma‐leukosis virus/tumor virus A system to examine the impact of Fn14 expression on glioma development and pathobiology. We found that the sole addition of Fn14 to an established oncogenic cocktail previously shown to generate proneural‐like gliomas led to the development of highly invasive and lethal brain cancer with striking biological features including extensive pseudopalisading necrosis, constitutive canonical and noncanonical NF‐κB pathway signaling, and high plasminogen activator inhibitor‐1 (PAI‐1) expression. Analyses of HGG patient datasets revealed that high human PAI‐1 gene (SERPINE1) expression correlates with shorter patient survival, and that the SERPINE1 and Fn14 (TNFRSF12A) genes are frequently co‐expressed in bulk tumor tissues, in tumor subregions, and in malignant cells residing in the tumor microenvironment. These findings provide new insights into the potential importance of Fn14 in human HGG pathobiology and designate both the NF‐κB signaling node and PAI‐1 as potential targets for therapeutic intervention. Main Points This work demonstrates that elevated levels of the TWEAK receptor Fn14 in tumor‐initiating, neural progenitor cells leads to the transformation of proneural‐like gliomas into more aggressive and lethal tumors that exhibit constitutive NF‐κB pathway activation and plasminogen activator inhibitor‐1 overexpression.

Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ‐secretase activity

“…Fn14 upregulation helps to mediate local tissue responses including tissue remodeling and inflammation, for example during burn wound repair (Liu et al , 2019), but also controls proliferation, apoptosis, cell migration, and differentiation (Winkles, 2008; Poveda et al , 2021) and synapse function in the visual system (Cheadle et al , 2020). However, increased Fn14 levels or signaling are also linked to chronic diseases, such as most solid tumor types, acute kidney disease, fibrosis, Alzheimer's disease, and cerebral ischemia (Cheng et al , 2013; Perez et al , 2016; Hu et al , 2017; Wang et al , 2017; Connolly et al , 2021; Nagy et al , 2021). Thus, Fn14 is intensively tested as a drug target using monoclonal antibodies or immunotoxins targeted to Fn14 or fusion proteins encoding Fn14 decoy receptors, which improve pathology in various mouse models of disease, such as for lung tumors, triple‐negative breast cancer, tumor cachexia, and atherosclerosis (Yepes et al , 2005; Schapira et al , 2009; Michaelson et al , 2011; Wajant, 2013; Zhou et al , 2014; Johnston et al , 2015; Peng et al , 2018; Alvarez de Cienfuegos et al , 2020; Dancy et al , 2020; Wolf et al , 2021).…”

Fn14-Directed DART Nanoparticles Selectively Target Neoplastic Cells in Preclinical Models of Triple-Negative Breast Cancer Brain Metastasis

“…38 Our group recently reported that glioblastoma tumor-associated macrophages (TAMs) express Fn14 through analysis of single-cell RNA sequencing data. 27 Fn14 expression has also been detected in human monocyte cell lines, 39 peritoneal macrophages, and peripheral blood mononuclear cells. 40 These findings suggest that Fn14-targeted DART NPs may associate with Fn14-positive non-neoplastic cells in the tumor-immune microenvironment (TIME).…”

“…Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible 14 (Fn14), are members of the TNF and TNFR superfamilies, respectively, that are primarily involved in repair processes that occur following tissue injury . Fn14 expression is low in healthy tissues but upregulated in over a dozen solid tumors, including TNBC tumors and metastases, , and high Fn14 levels have been shown to correlate with advanced tumor stage and poor patient outcomes. ,− Importantly, Fn14 is also significantly overexpressed in BC BMs, where it has been identified as the most useful and accurate predictive biomarker of BM in luminal BC subtypes . The function of Fn14 in primary or metastatic BC is unclear; however, ectopic expression of Fn14 in TNBC cells stimulates cell migration and invasion, suggesting a potential metastasis-promoting function …”

“…The brain tumor (BT) microenvironment is composed of tissue-resident cells and a large proportion of recruited immune cells that, in the case of BC, can constitute up to 50% of the tumor mass . Our group recently reported that glioblastoma tumor-associated macrophages (TAMs) express Fn14 through analysis of single-cell RNA sequencing data . Fn14 expression has also been detected in human monocyte cell lines, peritoneal macrophages, and peripheral blood mononuclear cells .…”

Hydrogel on a Smart Nanomaterial Interface to Carry Therapeutics for Digitalized Glioma Treatment

“…Invasive glioma cells are resistant to clinical standard-of-care chemotherapy, along with radiation [ 15 ]. The emerging molecular target implicated in invasive glioma biology is the TNF receptor superfamily member named fibroblast growth factor-inducible 14 (Fn14) [ 5 , 38 ]. Additional, mural-like tumor cells differentiate from GSCs.…”