Biology subjects

Evensen, K. G.

Publications and source records attributed to Evensen, K. G..

5 recordsLinked to original sources

bioRxiv2026

Disruption of the ARID1A-containing SWI/SNF complex reprograms tumor-associated macrophages and enhances immunotherapy response

Tumor-associated macrophages (TAMs) contribute to tumor immune evasion and therapeutic resistance. However, the epigenetic and transcriptional regulators that control TAM function remain largely unidentified. Here we investigated the role of the SWI/SNF chromatin remodeling complex in TAMs and whether disruption of SWI/SNF function in TAMs could improve immunotherapy. Pharmacologic inhibition of SWI/SNF ATPase activity improved the efficacy of checkpoint blockade immunotherapy, slowing tumor growth and reprogramming transcription broadly in tumor cells, tumor-infiltrating lymphocytes, and TAMs. To define the role of SWI/SNF in TAMs specifically, we genetically deleted the SWI/SNF subunit Arid1a in myeloid cells and found this was sufficient to suppress tumor progression and enhance checkpoint blockade response. Epigenomic and single cell analyses indicated that SWI/SNF inhibition and ARID1A deletion in TAMs reduced accessibility at enhancers of genes associated with poor prognosis, such as Spp1, and increased accessibility at promoters of interferon-stimulated genes (ISGs). CD86 was elevated on ARID1A-deficient TAMs and the enhanced immunotherapy response required CD86 costimulation and CD8+ T cells. These findings establish ARID1A-dependent chromatin remodeling as a determinant of TAM gene expression programs and show that disruption of myeloid SWI/SNF function improves checkpoint blockade immunotherapy via TAM reprogramming.

cancer biology↗

bioRxiv2026

Cellular senescence is associated with age-related loss of liver zonation and hepatocyte function

The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by "expansion" of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A "no-zone" hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

cell biology↗

bioRxiv2025

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.

cell biology↗

bioRxiv2025

Med14 phosphorylation shapes genomic response to GLP-1 Agonist

Under feeding conditions, release of glucagon-like peptide (GLP-1) from intestinal L cells promotes insulin secretion and pancreatic beta cell viability. Binding of GLP-1 to its cognate receptor on the beta cell surface results in induction of the cAMP signaling pathway, leading to the protein kinase A (PKA) mediated phosphorylation of CREB and induction of CREB target genes. By contrast with the acute effects of this pathway on immediate early CREB target genes, which attenuate the cAMP-CREB response, sustained exposure of beta cells to the stable GLP-1 receptor agonist Exendin-4 stimulates the expression of beta cell specific CREB target genes with delayed kinetics. In a proteomic screen for transcriptional co-regulators that mediate the long-term effects of GLP-1 analogs, we identified Med14, a backbone subunit of the Mediator complex. Exposure to Exendin-4 stimulates Med14 phosphorylation at Ser983, corresponding to a conserved PKA recognition site (RRXS) that is located within an intrinsically disordered region of Med14. Phosphorylation of Med14 by PKA is essential for maintenance of enhancers that drive induction of beta cell-specific and diabetes-linked genes. Mutation of Med14 at Ser983 to alanine decreased beta cell numbers and repressed Exendin-4 induced gene regulation in primary mouse beta cells. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.

genomics↗

bioRxiv2024

Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer

Age is a major risk factor for liver cancer, as is the case for most adult human cancers. However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytes in vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of "precarious balance", due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN-signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences.

cancer biology↗