Experimental and Molecular Medicine最新文献

Understanding the early stages of carcinogenesis requires detailed insight into the abnormalities present in normal cells before cancer onset. In the past, it was difficult to analyze genomic abnormalities in small clones in normal tissues. However, recent technological advances in genomic analysis have shed light on the process of accumulation of somatic mutations in normal cells, which is driven by factors such as aging and environmental influences. Even in normal tissues, clones that have acquired driver mutations-either directly contributing to carcinogenesis or adapting to specific pathological or genetic backgrounds-are frequently selected, leading to clonal expansion. Normal cells undergo clonal evolution into cancer cells over several decades, with the initial acquisition of a driver mutation occurring in early life. Here this review presents recent findings concerning the accumulation of somatic mutations in normal cells, acquisition of driver mutations and clonal evolution toward cancer.

Clinical studies have shown a paradox of the usage of platelet-rich plasma (PRP) on treating fatty infiltration (FI) in injured muscles. However, the underlying reason is still unclear, partially owing to unknown effective components and confounders. Here we found that exosomes derived from PRP (thereafter named PRP-exos) most efficiently prevented FI in injured muscles by inhibiting the adipogenesis of fibro-adipogenic progenitors (FAPs). Importantly, we found aging largely impaired the therapeutic effects of PRP-exos. Mechanistically, miRNA cargoes in PRP-exos mediated the effects of PRP-exos on adipogenesis of FAPs as well as FI in injured muscles, of which, hsa-let-7f-5p and hsa-miR-16-5p were the two most important components. TGFBR3 was identified as a new cotarget gene of these two miRNAs and a new regulator to control the adipogenesis of FAPs. The FI in muscles can be significantly reduced after conditional knockout of TGFBR3 in FAPs. In addition, we further investigated that TGFBR3 regulated the activation of ERK-PPARγ pathway through directly inducing the degradation of KRT10, and thus impacted the adipogenesis of FAPs. Interestingly, PRP-exos or these two miRNAs can preserve the viability and promote the proregenerative supporting capacity of FAPs by targeting TGFBR3 to facilitate muscle regeneration. Collectively, our findings identified the effective components in PRP to inhibit FI and support muscle regeneration. Furthermore, the negative influence of aging on clinical applications of PRP cannot be neglected.

Hyperphosphorylated tau aggregation and neuroinflammation are hallmark pathologies of Alzheimer's disease (AD), with microglia playing a critical role in modulating these processes through maintaining immune homeostasis and clearing pathological tau, both of which depend on mitochondrial health. However, the mechanisms underlying microglial mitochondrial dysfunction in AD remain poorly understood, limiting therapeutic development. Hydrogen voltage-gated channel 1 (Hv1), expressed in microglia within the central nervous system, regulates intracellular pH and reactive oxygen species generation. Here we observe that Hv1 is upregulated in activated microglia in AD mouse models. Remarkably, Hv1 contributes to electron transport chain abnormalities, leading to mitochondrial oxidative stress, loss of mitochondrial membrane potential, impaired ATP production and deficient mitophagy in tau pathology. These deficits impair tau clearance through phagocytosis and autophagy but can be significantly reversed by the Hv1-specific inhibitor YHV98-4. Furthermore, YHV98-4 enhances microglia-to-neuron mitochondrial transfer, promoting the delivery of functional mitochondria to rescue neuronal damage and improve cognitive function. Collectively, our study underscores the pivotal role of Hv1 in microglial mitochondrial dysfunction in AD and identifies YHV98-4 as a promising therapeutic candidate.

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.