Biology subjects

Arner, E. N.

Publications and source records attributed to Arner, E. N..

6 recordsLinked to original sources

bioRxiv2026

Small Extracellular Vesicle Cargoes Associated with Lymph Node Metastasis in Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy in which cervical lymph node metastasis critically determines patient prognosis. Despite advances in clinical staging based on tumor size, depth of invasion, and nodal status, these parameters fail to capture the biological heterogeneity of HNSCC, leading to overtreatment or undertreatment, and significant morbidity. Emerging evidence implicates small extracellular vesicles (SEVs) as key mediators of tumor progression and promising biomarkers for metastatic potential. In this study, we performed iTRAQ-based proteomic profiling of SEVs from metastatic (MOC2) and nonmetastatic (MOC1) HNSCC mouse cell lines and identified multiple cargoes associated with metastatic processes, including angiogenesis, extracellular matrix remodeling, immune modulation, and perineural invasion. Further, we employed an immune-competent orthotopic mouse oral carcinoma (MOC) model to investigate how exosome biogenesis affects HNSCC metastasis. Loss of the exosome/SEV biogenesis protein HRS in MOC2 HNSCC cells impaired SEV formation in vitro and tumor growth and metastasis in vivo. Consistent with the SEV cargoes enriched in MOC2 EVs, immunohistochemical analyses of MOC2 tumors revealed reduced blood vessel and nerve density in HRS-deficient tumors. Analysis of candidate biomarker SEV cargoes in the circulating EVs from HPV-negative HNSCC patients revealed significant correlations of these proteins with metastatic status. Collectively, these findings identify SEV cargoes as potential functional mediators of metastasis and liquid biopsy biomarkers in HNSCC.

cancer biology↗

bioRxiv2025

Impaired oxidative phosphorylation drives primary tumor escape and metastasis

Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.

cancer biology↗

bioRxiv2024

Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism

SummaryWe show that the mitochondrial fatty acid synthesis gene Mecr shapes CD4+ T cell metabolism and function. It may be targeted in inflammatory diseases and provides rationale to consider the immunological state of patients with mitochondrial disease. Lipid metabolism is fundamental to CD4+ T cell metabolism yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid-associated genes essential for T cell subset functions. These screens established mitochondrial fatty acid synthesis (mtFAS) genes Mecr, Mcat and Oxsm as highly impactful. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Effector and memory T cells were reduced in Mecrfl/fl; Cd4cre mice, and MECR was required for activated CD4+ T cells to efficiently proliferate, differentiate, and survive. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced TCA intermediates, and accumulated intracellular iron, which contributed to cell death and sensitivity to ferroptosis. Importantly, Mecr-deficient T cells exhibited fitness disadvantages in inflammatory, tumor, and infection models. mtFAS and MECR thus play important roles in activated T cells and may provide targets to modulate immune functions in inflammatory diseases. The immunological state of MECR- and mtFAS-deficient patients may also be compromised.

immunology↗

bioRxiv2022

PD-1 is induced on tumor-associated macrophages in obesity to directly restrain anti-tumor immunity

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can also promote improved survival for some cancers3-5 and enhance responses to some immune checkpoint blockade therapies6-8. The role of the immune system in the obesity-cancer connection and how obesity influences immunotherapy, however, remain unclear. While PD-1 expression by macrophages has been described9-12, we found that obesity selectively induced PD-1 on macrophages and that PD-1 directly impaired macrophage function. Single cell RNA sequencing of murine colorectal carcinoma tumors showed obesity remodeled myeloid and T cell populations, with fewer clonally expanded effector T cells and increased abundance of PD-1+ tumor-associated macrophages (TAM). Cytokines and molecules associated with obesity, including IL-6, leptin, and insulin, and the unsaturated fatty acid palmitate, induced PD-1 expression on macrophages in a glycolysis-dependent manner. PD-1+ TAMs had increased mitochondrial respiration and expression of genes regulating oxidative phosphorylation, lipid uptake and cell cycle while PD-1- TAMs showed greater signatures of phagocytosis and antigen presentation to T cells. These patterns were directly regulated by PD-1, as recombinant PD-L1 reduced macrophage glycolysis and phagocytic capacity, and this was reversed with blocking PD-1 antibody. Conversely, PD-1-deficient Pdcd1-/- TAMs had high rates of glycolysis, phagocytosis, and expression of MHC-II. Myeloid-specific PD-1 deficiency correlated with slower tumor growth, enhanced TAM antigen presentation capability, and increased CD8 T cell activation together with reduced markers of exhaustion. These findings show metabolic signaling in obesity induces PD-1-mediated suppression of TAM function and reveal a unique macrophage-specific mechanism to modulate immune tumor surveillance and checkpoint blockade. This may contribute to increased cancer risk yet improved response to PD-1 blockade in TAM-enriched tumors and obesity.

immunology↗

bioRxiv2022

AXL-TBK1 driven nuclear AKT3 promotes metastasis

Epithelial-to-mesenchymal transition (EMT) contributes to tumor cell survival, immune evasion, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a higher likelihood of metastasis. AXL, a receptor tyrosine kinase, drives EMT and is implicated in tumor progression, metastasis, and therapy resistance in multiple cancer types including pancreatic cancer and breast cancer. TANK-binding kinase 1 (TBK1) is central to AXL-driven EMT yet, the mechanism of how TBK1 induces EMT remains unclear. Here, we report that AXL activation stimulates TBK1 binding and phosphorylation of AKT3. TBK1 activation of AKT3 drives binding and phosphorylation of slug/snail resulting in protection from proteasomal degradation and translocation of the complex into the nucleus. We show that nuclear translocation of AKT3 is required for AXL-driven EMT and metastasis. Congruently, nuclear AKT3 expression correlates with worse outcome in aggressive breast cancer. To advance AKT3 as a therapeutic target, an AKT3-isoform selective allosteric small molecule inhibitor, BGB214, was developed. BGB214 inhibits AKT3 nuclear translocation, EMT-TF stability, AKT3-mediated invasion of breast cancer cells and reduces tumor initiation in vivo. Our results suggest that AKT3 nuclear activity is an important feature of AXL-driven epithelial plasticity and that selective AKT3 inhibition represents a novel therapeutic avenue for treating aggressive cancer. SignificanceNuclear AKT3 activity is an important feature of AXL-TBK1 driven EMT and metastasis, thus selective AKT3 targeting represents a novel approach to treat aggressive cancer.

cancer biology↗

bioRxiv2018

Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS, which is critical for the biology of PDA progression. Direct inhibition of KRAS through pharmacological means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. We investigated the contribution of TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, to PDA progression. We report that higher levels of TBK1 mRNA are associated with poorer overall survival in human PDA patients and that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner. These findings demonstrate that TBK1 is central to an Axl-driven epithelial-mesenchymal transition in KRAS-mutant PDA and suggest that interruption of the Axl-TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease.

cancer biology↗