Experimental and Molecular Medicine最新文献

The majority of patients with lung cancer are diagnosed at an advanced stage, with a substantial proportion exhibiting signs of brain metastases (BMs). BM is associated with debilitating symptoms, including headaches, seizures and neurological or cognitive impairments, which severely impact the quality of life of patients. Despite considerable advancements in lung cancer treatment modalities, the management of BM remains challenging due to the complex cellular and structural nature of the blood-brain barrier and resistance driven by acquired genetic mutations. Non-small cell lung cancer (NSCLC) is characterized by diverse genetic alterations. The application of immunotherapy has successfully enhanced antitumor immune responses within the tumor microenvironment (TME) of affected patients. The intricate interplay between NSCLC cells and the TME plays a critical role in the pathogenesis of BM. This review focuses on the brain-specific TME and its exploitation by tumor cells to establish metastases through strategic, site-specific mechanisms. The reciprocal molecular interactions, immune modulation and adaptation of NSCLC cells to the brain metastatic niche are central to this process. A deeper understanding of the complex crosstalk between tumor cells and TME is essential for devising more effective and targeted therapeutic interventions for BM.

Tumor recurrence and metastasis are largely attributed to dormant tumor cells receiving reactivation signals, particularly those originating from the tumor microenvironment. However, the detailed mechanisms of dormant tumor cell reactivation in salivary gland adenoid cystic carcinoma (SACC) remain largely unknown. Here our data revealed that autophagy is activated in dormant SACC cells but becomes downregulated once these cells are reactivated, and that cancer-associated fibroblast (CAF)-mediated autophagy promotes dormant SACC cells to resume proliferation and escape dormancy. Mechanistically, PLIN2 encapsulated in CAFs-derived extracellular vesicles promoted the initial stage of autophagy through the endoplasmic reticulum stress signaling pathway, and directly bound to p62 to promote lipid droplet degradation through the lipophagy pathway, which provided energy for the reactivation of dormant SACC cells. Moreover, we confirmed that PLIN2 expression was remarkably correlated with poor survival in patients with SACC. Finally, we verified that the combination of tozasertib and PLIN2 was stable through molecular docking and molecular dynamics simulation, indicating that tozasertib has the potential to serve as a targeted PLIN2 drug for CAFs in SACC. Our findings suggest that targeting PLIN2 and autophagy inhibition as part of primary SACC treatment may effectively eliminate dormant tumor cells and prevent SACC recurrence.

Chemoresistance remains a major challenge in pancreatic ductal adenocarcinoma (PDAC). Glutamine sustains drug resistance and shapes the immunosuppressive tumor microenvironment; however, the underlying mechanisms remain unclear. Identifying key regulators that drive both gemcitabine resistance and immune evasion is crucial for improving theapeutic outcomes in PDAC. Here we identified solute-carrier family 6 member 14 (SLC6A14) as the central regulator of glutamine metabolism that drives gemcitabine resistance. SLC6A14-mediated glutamine metabolism facilitated α-ketoglutarate production, activating mTOR/NF-κB signaling to upregulate PD-L1 expression, playing a central role in immune evasion. Moreover, SLC6A14 induced CXC motif chemokine ligand 8 secretion via synaptotagmin-like 4-mediated exocytosis, paracrinally activating CXCR2 signaling in cancer-associated fibroblasts to enhance mitochondrial fission and amino acid recycling, supporting PDAC progression. Targeting SLC6A14 with α-methyl-tryptophan enhanced gemcitabine sensitivity, suppressed PD-L1 driven immune evasion and reduced tumor growth, metastasis and glutamine production in vivo. These findings underscore SLC6A14 as a pivtoal mediator of glutamine-driven gemcitabine resistance and immune evasion in PDAC. Therapeutic strategies targeting SLC6A14, either alone or in combination with PD-L1 blockade, hold promise for overcoming chemoresistance and enhancing antitumor immunity in gemcitabine-resistant pancreatic cancer.

Melanosomes are highly specialized organelles responsible for melanin synthesis, storage and transport in melanocytes, playing a central role in pigmentation and skin homeostasis. Although melanosome biogenesis and trafficking have been well characterized, emerging evidence emphasizes the importance of melanosome degradation in regulating pigment levels. Among the degradation pathways, melanophagy-a selective form of autophagy targeting melanosomes-has recently emerged as an important mechanism for the turnover of damaged, immature, or excess melanosomes. Here we highlight current insights into melanophagy mechanisms, including molecular regulators and signaling pathways. We also discuss the potential of modulating melanophagy as a novel cosmetic or therapeutic approach for managing hyperpigmentation, offering an alternative to traditional strategies focused solely on inhibiting melanin synthesis. By emphasizing the role of organelle clearance, melanophagy provides a new paradigm in the regulation of skin pigmentation.

Circulating tumor cell (CTC) clusters, key in metastasis, rely on intercellular junctions for stability. However, the specific mechanisms governing intercellular connections within CTC clusters and the strategy targeting intercellular junctions to break CTC clusters remain elusive. Anticoagulants, commonly used to manage tumor-associated thrombosis, may potentially serve as CTC cluster dissociators, but their effects and mechanisms in inhibiting tumor metastasis are unclear. Hirudin, an anticoagulant peptide was used as a tool drug and found to inhibit breast tumor lung retention and colonization through its disruption of CTC clusters rather than directly inhibiting cell migration. Further research confirmed that within CTC clusters, desmosome junctions play a dominant role in maintaining CTC cluster formation with high expression of related proteins, while adhesion junctions express rarely. Desmoglein 2 (DSG2) mediates conversion between desmosome and adhesion junctions in CTC clusters. When DSG2 is highly expressed, the intercellular junctions within the CTC clusters are mainly composed of desmosomes. Reversely, low expression of DSG2 results in adhesion junctions. In addition, hypoxia-inducible factor-1 alpha (HIF-1α) positively controls DSG2-mediated desmosome junctions. Inhibiting HIF-1α promotes the conversion from desmosome to adhesion junctions, destabilizing CTC clusters. Hirudin inhibits hematogenous metastasis of breast cancer through suppression of HIF-1α-controlled DSG2-mediated desmosome junctions, ultimately leading to the disintegration of CTC clusters. Our findings highlight the therapeutic potential of targeting HIF-1α-controlled DSG2-mediated desmosome junction conversion and position hirudin as a promising CTC clusters dissociator optimized for the clinical prevention of breast cancer metastasis.

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies, with limited efficacy of systemic therapies due to poor survival benefit and drug resistance. Dolichyl-diphosphooligosaccharide-protein glycosyltransferase noncatalytic subunit (DDOST), a critical component of oligosaccharyltransferase (OST), is upregulated in multiple cancers, yet its role in HCC is unclear. Here we demonstrate that DDOST expression is elevated in HCC tissues and correlated with poor prognosis. Functional studies showed that DDOST knockdown suppressed cell proliferation, induced cell cycle arrest and enhanced their lenvatinib sensitivity both in vitro and in vivo. Mechanistically, DDOST depletion impaired EGFR N-glycosylation, suppressing downstream AKT, ERK5 and ERK1/2 signaling, thereby sensitizing HCC cells to lenvatinib. Loss of DDOST also reduced PD-L1 glycosylation. Furthermore, the OST inhibitor NGI-1 and NGI-1-loaded nanoparticles exerted potent antitumor effects and further augmented the efficacy of lenvatinib and immunotherapy. These findings highlight DDOST as a promising therapeutic target to improve treatment outcomes in HCC.

DCSTAMP serves as a critical fusogenic protein orchestrating cell-cell fusion during osteoclastogenesis. The disruption of DCSTAMP functionality preserves preosteoclasts, thereby augmenting bone mass through both anabolic and anti-catabolic mechanisms. Despite its therapeutic potential, specific DCSTAMP inhibitors remain undiscovered. Here we used structure-based virtual screening utilizing AlphaFold predictions to identify a novel small molecule, E8431, which selectively targets the endoplasmic domain of DCSTAMP. In vitro investigations confirm E8431's capacity to impede preosteoclast fusion, concurrently inhibiting bone resorption while stimulating PDGFBB secretion, thus promoting osteogenic and angiogenic processes. We further elucidated a previously uncharacterized DCSTAMP signaling cascade involving DCSTAMP-RAP1B interaction, which activates RAP1-RAC1 signaling-dependent cytoskeletal reorganization. Notably, E8431 demonstrates potent inhibitory effects on this DCSTAMP-RAP1B molecular interface. Moreover, E8431 administration effectively attenuates ovariectomy-induced bone loss in murine models without apparent toxicity, underscoring its potential as a therapeutic agent for osteoporosis.

CD169⁺ macrophages, a unique subset of macrophages that cannot be simply defined as M1 or M2 macrophages, have been reported to be associated with various autoimmune diseases. However, the role of CD169⁺ macrophages in autoimmune hepatitis (AIH) is largely unknown. Here we found that the infiltration of CD169⁺ macrophages increased in the liver of patients with AIH and strongly positively correlated with inflammation degree. In a mouse model, depletion of CD169⁺ macrophages ameliorated ConA-induced acute liver injury. Immune homeostasis was also improved when CD169⁺ macrophages were depleted, as the infiltration of monocytes, macrophages and T cells decreased. Bone marrow-derived Ly6C^hiCD169⁺ macrophages were further identified as the crucial subset in AIH. Next, we found that CD169⁺ macrophages were IFNγ-responsive and IFNγ could induce the expression of CD169. In response to the IFNγ signal, CD169⁺ macrophages actively secrete chemokine (C-C motif) ligand (CCL12), thus recruiting CCR2⁺ monocytes and macrophages to exacerbate AIH. Finally, neutralizing CCL12 improved AIH. Our results suggest that bone marrow-derived CD169⁺ macrophages, the key subset of macrophages in AIH, actively secrete CCL12 in response to IFNγ to recruit CCR2⁺ monocytes and macrophages, thus exacerbating AIH. The CD169⁺ macrophages are a potential therapeutic target in AIH.

Although considerable research has focused on enhancing the apoptotic function of BAX for several decades, inhibition of its functionality remains relatively underexplored, despite intensive BAX activation occurring in various neurodegenerative diseases. Here we present a protein engineering approach to modulate BAX integration into the mitochondrial outer membrane, establishing a tunable strategy for antiapoptosis. Utilizing optogenetic methods that employ cryptochrome 2 and its binding partner cryptochrome-interacting basic helix loop helix 1, we achieved precise spatial control over BAX localization, a critical determinant of its function. Our results demonstrate that the engineered BAX variant is effectively incapacitated in its apoptotic function while also modulating endogenous BAX activity to enhance cellular resistance to apoptosis. These findings not only advance our understanding of BAX regulation but also offer promising prospects for the development of therapeutic strategies against apoptosis-related diseases.