Signal Transduction and Targeted Therapy最新文献

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.

The intricate relationship between the microbiota and cancer has recently emerged as a pivotal area of research, highlighting their critical roles in carcinogenesis, progression, and prognosis. With the increasing recognition of the therapeutic potential of the microbiota in cancer, there is an urgent need to understand the diverse impacts of different microbiota on tumors and explore innovative strategies to harness their benefits. For the first time, this review traces the historical evolution of microbiota-cancer studies, from early observations of microbial presence in cancers to landmark discoveries linking specific microorganisms to carcinogenesis. Furthermore, this study delves into the molecular mechanisms underlying microbiota-mediated cancer progression to elucidate the modulatory roles of oncogenic pathways, immune responses, and tumor metabolism. We also discuss the dual roles of the microbiota in promoting and inhibiting cancer, highlighting its potential as both a facilitator of tumor growth and a target for therapeutic intervention. In addition, this review highlights the mechanism by which the microbiota mediates the response to anticancer immunotherapy, chemotherapy, and radiotherapy. Simultaneously, emerging anticancer strategies targeting microbiota (e.g., probiotics, antibiotics, and fecal microbiota transplantation) have been explored alongside U.S. Food and Drug Administration-approved drugs and ongoing clinical trials. Finally, this review outlines future directions in this field, emphasizing the need for personalized approaches to harness the anticancer potential of the microbiota. The interpretations in this review are expected to establish a stereoscopic, comprehensive framework for advancing research and clinical applications in microbiota-targeted oncology.