Signal Transduction and Targeted Therapy最新文献

Cancer metastasis is the primary cause of cancer-related mortality, yet effective treatments remain limited. There is an urgent need to develop novel therapeutic strategies to combat metastasis. In this study, we demonstrate that the bacterial intracellular signaling molecule cyclic di-GMP (c-di-GMP, or cdG) exerts a potent inhibitory effect on cancer metastasis, particularly in metastatic breast cancer, via both in vitro and in vivo models, with little toxicity to mice. Interestingly, this antimetastatic function is achieved by suppressing the NF-κB signaling pathway, which is important for cancer progression and metastasis, but independent of STING, a previously identified c-di-GMP sensor and NF-κB regulator in mammalian cells. Surprisingly, c-di-GMP inhibits NF-κB activity (p-p65) by directly binding to the proteasome 26S subunit non-ATPase 3 (PSMD3) that we identified as a new TBK1-binding activator, and disrupting the interaction between PSMD3 and TBK1. This PSMD3-TBK1 interaction boosts the phosphorylation and activation of TBK1, representing a noncanonical function of PSMD3 distinct from its established role in proteasomal degradation. Significantly, PSMD3 is highly expressed in malignant and metastatic breast cancers, particularly triple-negative breast cancer. The compelling evidence strongly suggests PSMD3 as a promising target for developing a therapy against metastatic breast cancer. These findings underscore the high potential of c-di-GMP as a safe and effective therapeutic agent for metastatic cancers by targeting the PSMD3-TBK1-NF-κB pathway.

While progress has been made in transcriptomic profiling of the human brain, functional characterization of brain regions and their interactions on the basis of regional protein expression remains limited. Here, we constructed a proteomic map from thirteen anatomical brain regions of eight cadaver donors to elucidate region-specific protein expression patterns and their implications for brain function. The results underscore the interconnectivity of the four cerebral lobes, suggesting facilitated information integration through large-scale neural networks. We propose a three-module framework (cortical integration module [frontal lobe, temporal lobe, parietal lobe, occipital lobe], limbic-relay network [amygdaloid nucleus, hippocampus, thalamus/hypothalamus], and midline regulatory axis [thalamus/hypothalamus, corpus callosum, ventricles, optic chiasm]) and provide molecular evidence supporting the potential involvement of the midline regulatory axis, brainstem, and cerebellum in higher-order cognitive functions. The midline regulatory axis may play a critical but underexplored role in neurodevelopment, interregional signaling, and structural homeostasis, potentially through efficient synaptic function, energy metabolism, and extracellular matrix integrity. This analysis may enhance the understanding of brain physiology and highlight the need to integrate proteomic and transcriptomic approaches in the study of brain function and neurological disorders.

The high mortality caused by severe COVID-19 poses great challenges to the public health. However, the underlying pathogenesis of severe cases remains unclear. Here, we find that SARS-CoV-2 infection boosts CD147 inducible up-regulation in the lung tissues of virus-infected rhesus macaques coupled with down-regulated membrane-bound ACE2, which conduces to extended virus infection and severe pathological lesions. Specifically, SARS-CoV-2 infection enhances the expression of transcriptional factor aryl hydrocarbon receptor and facilitates its nucleus translocation, which causes CD147 gene transcription and its up-regulation in protein level, thereby leading to virus susceptibility of the hosts and extended virus infection. Meanwhile, SARS-CoV-2 infection triggers immune imbalance of lung tissues by promoting cell death of CD4 + T cells and B cells and mediating abnormal cell-cell communications, especially for M2 macrophages. Meplazumab, a humanized anti-CD147 antibody, effectively inhibits virus entry and cytokine level, and restores immune balance in the lung tissues of virus-infected rhesus macaque model. Importantly, we further present the cryo-EM structure of CD147-spike complex, and identify five pairs of functional residues for their interaction, which could be interrupted by Meplazumab via steric hindrance effect. Our findings provide direct evidence for CD147-SARS-CoV-2 spike interaction and uncover the pathogenesis of severe COVID-19 caused by CD147-mediated extended virus infection.

Inactivating vascular endothelial growth factor receptor (VEGFR) may improve the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). The ATTENTION study (phase II, open-label, randomized, multicenter trial (Registration number: ChiCTR2100047453), evaluated the efficacy and safety of aumolertinib plus apatinib vs. aumolertinib alone in untreated, EGFR-mutant, advanced NSCLC. The primary endpoint was the 18-month PFS rate. Across 18 centers in China, 104 patients were enrolled to receive aumolertinib alone (n = 51) or with apatinib (n = 53). At a median follow-up duration of 19.4 months, aumolertinib plus apatinib outperformed aumolertinib alone in terms of the 18-month progression-free survival (PFS) rate (74% vs. 50%, P = 0.036), median PFS (not reached [NR] vs. 20.1 months, hazard ratio [HR] = 0.41, P = 0.017), and objective response rate (79% vs. 59%, P = 0.024). No grade 4/5 treatment-related adverse effects (TRAEs) were observed, whereas grade 3 TRAEs occurred in 38% vs. 27% of patients, with hypertension (11%) and platelet count decrease (9%) being most common in the combination arm. Exploratory analysis revealed that PFS benefits from aumolertinib plus apatinib predominantly in those with TP53 mutations. As an infusion-free option, aumolertinib plus apatinib demonstrated PFS benefits with manageable safety in patients with untreated, EGFR-mutant, advanced NSCLC.

Radiotherapy remains a mainstay of cancer treatment. However, radiotherapy can also elicit acute and chronic adverse effects, including dermal inflammation and skin fibrosis. A comprehensive understanding of the underlying fibrotic processes remains elusive, and currently, no established treatment options exist. Canonical Wnt signaling has emerged as a significant player in fibrotic conditions. The Dickkopf (DKK) protein family comprises key modulators of Wnt signaling. To define the function of DKK3 in radiation-induced skin damage, we combined complementary in vivo and in vitro approaches, including a 3D human skin model, mice with cell-type-specific Dkk3 deletions, and irradiated human skin specimens. Our study revealed the pivotal role of DKK3 in regulating the response of the skin to radiation, with diminished DKK3 significantly mitigating radiation-induced skin damage. We found that radiation increases DKK3 expression in basal keratinocytes, leading to elevated ROS levels, TGF-β-mediated Wnt activation, epidermal hyperplasia, and subsequent skin fibrosis. Increased keratinocyte expression of DKK3 also drives macrophage polarization toward a CD163^highCD206^high profibrotic M2 phenotype, activating myofibroblasts and leading to fibrosis. Notably, DKK3 deficiency in keratinocytes markedly reduces radiation-induced dermal hyperplasia and fibrosis, identifying DKK3 as a key regulator of cutaneous radiation responses. These findings position DKK3 as a promising upstream modulator of TGF-β signaling for mitigating radiation-induced dermatitis and fibrosis, with potential relevance to other fibrotic diseases.