Publications

AXL-TBK1 driven AKT3 activation promotes metastasis

Emily N Arner et al.

Sci Signal. 2024 Dec 17;17(867):eado6057. doi: 10.1126/scisignal.ado6057. Epub 2024 Dec 17.

The receptor tyrosine kinase AXL promotes tumor progression, metastasis, and therapy resistance through the induction of epithelial-mesenchymal transition (EMT). Here, we found that activation of AXL resulted in the phosphorylation of TANK-binding kinase 1 (TBK1) and the downstream activation of AKT3 and Snail, a transcription factor critical for EMT. Mechanistically, we showed that TBK1 directly bound to and phosphorylated AKT3 in a manner dependent on the multiprotein complex mTORC1. Upon...

Engineering and Targeting Neutrophils for Cancer Therapy

Adv Mater. 2024 May;36(19):e2310318. doi: 10.1002/adma.202310318. Epub 2024 Feb 20.

Neutrophils are the most abundant white blood cells in the circulation and act as the first line of defense against infections. Increasing evidence suggests that neutrophils possess heterogeneous phenotypes and functional plasticity in human health and diseases, including cancer. Neutrophils play multifaceted roles in cancer development and progression, and an N1/N2 paradigm of neutrophils in cancer is proposed, where N1 neutrophils exert anti-tumor properties while N2 neutrophils display tumor-supportive and immune-suppressive functions. Selective activation of beneficial neutrophil population and targeted inhibition or re-polarization of tumor-promoting neutrophils has shown an important potential in tumor therapy. In addition, due to the natural inflammation-responsive and physical barrier-crossing abilities, neutrophils and their derivatives (membranes and extracellular vesicles (EVs)) are regarded as advanced drug delivery carriers for enhanced tumor targeting and improved therapeutic efficacy. In this review, the recent advances in engineering neutrophils for drug delivery and targeting neutrophils for remodeling tumor microenvironment (TME) are comprehensively presented. This review will provide a broad understanding of the potential of neutrophils in cancer therapy.

Stress biology: Complexity and multifariousness in health and disease

Cell Stress Chaperones. 2024 Feb;29(1):143-157. doi: 10.1016/j.cstres.2024.01.006. Epub 2024 Feb 3.

Preserving and regulating cellular homeostasis in the light of changing environmental conditions or developmental processes is of pivotal importance for single cellular and multicellular organisms alike. To counteract an imbalance in cellular homeostasis transcriptional programs evolved, called the heat shock response, unfolded protein response, and integrated stress response, that act cell-autonomously in most cells but in multicellular organisms are subjected to cell-nonautonomous regulation. These transcriptional programs downregulate the expression of most genes but increase the expression of heat shock genes, including genes encoding molecular chaperones and proteases, proteins involved in the repair of stress-induced damage to macromolecules and cellular structures. Sixty-one years after the discovery of the heat shock response by Ferruccio Ritossa, many aspects of stress biology are still enigmatic. Recent progress in the understanding of stress responses and molecular chaperones was reported at the 12th International Symposium on Heat Shock Proteins in Biology, Medicine and the Environment in the Old Town Alexandria, VA, USA from 28th to 31st of October 2023.

Embigin deficiency leads to delayed embryonic lung development and high neonatal mortality in mice

iScience. 2024 Jan 15;27(2):108914. doi: 10.1016/j.isci.2024.108914. eCollection 2024 Feb 16.

Embigin (Gp70), a receptor for fibronectin and an ancillary protein for monocarboxylate transporters, is known to regulate stem cell niches in sebaceous gland and bone marrow. Here, we show that embigin expression is at high level during early mouse embryogenesis and that embigin is essential for lung development. Markedly increased neonatal mortality of Emb-/- mice can be explained by the compromised lung maturation: in Emb-/- mice (E17.5) the number and the size of the small airways and distal airspace are significantly smaller, there are fewer ATI and ATII cells, and the alkaline phosphatase activity in amniotic fluid is lower. Emb-/- lungs show less peripheral branching already at E12.5, and embigin is highly expressed in lung primordium. Thus, embigin function is essential at early pseudoglandular stage or even earlier. Furthermore, our RNA-seq analysis and Ki67 staining results support the idea that the development of Emb-/- lungs is rather delayed than defected.

Programmable NIR Responsive Nanocomposite Enables Noninvasive Intratympanic Delivery of Dexamethasone to Reverse Cisplatin Induced Hearing Loss

Rawand A Mustaf et al.

Adv Sci (Weinh). 2024 Nov 21:e2407067. doi: 10.1002/advs.202407067. Online ahead of print.

Local intratympanic drug delivery to the inner ear possesses significant otological clinical promise as cisplatin-induced hearing loss (CIHL) therapy, inducing significantly less side effects than systemic drug delivery. However, the multiple detoured barriers, round window membrane (RWM) and poorly controlled drug release hinder successful non-invasive drug delivery through intratympanic administration (IT). Here, a novel near-infrared (NIR) responsive nanocomposite functionalized with saponin,...

Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis

Silvia Sabatini et al.

Cell Rep Med. 2024 Nov 19;5(11):101820. doi: 10.1016/j.xcrm.2024.101820.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6-²H(2)-glucose, U-²H(5)-glycerol) and liver-specific...