Jianyu Wang

Metabolic reprogramming is one of the eight hallmarks of cancer, and in lung cancer, it is notably linked to ferroptosis-related lipid metabolism. Cancer stem cells, regarded as the initiating cells of cancer, can extensively influence the tumor microenvironment (TME). Nevertheless, their role in metabolic reprogramming within lung adenocarcinoma (LUAD) remains incompletely explored. In this study, through molecular biology experiments including RNA-seq, proteomics, RNA pulldown, and PCR, we discovered a novel and intricate mechanism by which the lncRNA ROLLCSC, derived from extracellular vesicles (EVs) of LUAD stem cells, regulates the tumor TME. Mechanistically, lncRNA ROLLCSC can interact with CDC42, a GTPase protein, mediating a positive feedback loop that promotes the entry of more EVs into recipient lung cancer cells (LLC). FTO-mediated m6A demethylation enhances the stability of ROLLCSC, which is recognized by the reader protein IGF2BP2 in recipient LLC cells. Most importantly, lncRNA ROLLCSC can reshape the lipid metabolism of LLC cells by targeting ACSL4 and Slc25a11, thereby enhancing their resistance to ferroptosis. Clinically, ROLLCSC and its targets are associated with distinct tumor expression patterns and have prognostic significance. Overall, our study elucidates how the lncRNA ROLLCSC derived from cancer stem cell (CSC)-derived EVs is efficiently transported to LUAD cells, subsequently reshaping the lipid metabolism of recipient cells and enhancing their resistance to ferroptosis.

Background/Objectives: Melanoma, characterized by high rates of metastasis and recurrence, is a particularly aggressive malignant tumor. The underlying mechanisms driving its progression remain enigmatic. The close interplay between tumor and non-tumor cells is pivotal, significantly shaping the tumor microenvironment. Extracellular vesicles emerge as a crucial vector influencing this environment, as they can modulate cellular mechanisms and biological functions—marking a key frontier in tumor mechanism research. However, the potential impact of intercellular communication on tumor cell biology remains largely unexplored. Methods: In the study, we employed a pair of cell lines derived from melanoma M14 cells, designated as highly metastatic cells (POL cells) and the low metastatic cells (OL cells), and elucidate their characteristics. Results: Our findings revealed that POL cells can potentiate the metastatic potential of OL cells through the transfer of extracellular vesicles, which harbor functional microRNAs, specifically miR-23a-5p in this context. Upon entering OL cells, the EV-miR-23a-5p orchestrates changes in the m6A modification levels of the mRNA of tumor suppressor genes Mtus1 and Prrg4. Conclusions: This modulation subsequently influences the expression of these genes and, in turn, the invasive behavior of OL cells.

Metabolic remodeling driven by high-risk human papillomavirus (hrHPV) infection is a hallmark of cervical cancer (CC), yet how metabolites feedback to regulate viral oncogenic programs and promote tumor progression remains elusive. The recent discovery of lactate-induced histone lactylation, which modulates chromatin accessibility, offers a potential mechanism to address this gap. This study utilized integrated single-cell RNA sequencing (scRNA-seq), pan-lactylation (Pan-Kla) and site-specific CUT&Tag, ATAC-seq, and RNA-seq data to systematically characterize the lactylation landscape in CC. The biological functions of the "glycolysis-lactate-lactylation" axis were evaluated through clinical sample validation, in vitro functional assays, and in vivo models of subcutaneous tumorigenesis and lymph node metastasis. Mechanistically, histone pan-lactylation synergizes with H3K27ac to significantly enhance the chromatin accessibility of host oncogenes and the HPV16 Upstream Regulatory Region (URR). Notably, even under conditions of compensatory increases in acetylation, the loss of lactylation was sufficient to induce a significant reduction in chromatin accessibility and transcriptional repression. Comprehensive mapping of multiple lactylation sites further revealed a sophisticated labor division, where diverse sites cooperatively yet specifically regulate distinct oncogenic programs. Among these, H3K18la was identified as the predominant modification associated with tumor metastasis and poor clinical prognosis. Finally, this study reveals a lactate-mediated positive feedback loop: HPV infection induces glycolysis to produce lactate, which subsequently triggers histone lactylation to further drive E6/E7 transcription, systematically amplifying oncogenic signaling. In summary, our findings identify the "virus-metabolism-epigenetic" axis as a driver of CC progression, providing new insights into precision therapy for cervical cancer.

The mean survival of metastatic lung adenocarcinoma is less than 1 year, highlighting the urgent need to understand the mechanisms underlying its high mortality rate. The role of Extracellular vesicles (EVs) in facilitating the interactions between cancer cells and the metastatic microenvironment has garnered increasing attention. Previous studies on the role of EVs in metastasis have been primarily focused on cancer cell-derived EVs in modulating the functions of stromal cells. However, whether cancer stem cells (CSCs) can alter the metastatic properties of non-CSC cells, and whether EV crosstalk can mediate such interaction, have not been demonstrated prior to this report. In the present study, we integrated multi-omics sequencing and public database analysis with experimental validation to demonstrate, for the first time, the exosomal Mir100hg, derived from CSCs, could enhance the metastatic potential of non-CSCs both in vitro and in vivo. Mechanistically, HNRNPF and HNRNPA2B1 directly binds to Mir100hg, facilitating its trafficking via exosomes to non-CSCs. In non-CSCs, Mir100hg upregulates ALDOA expression, subsequently leading to elevated lactate production. Consequently, the increased lactate levels enhance H3K14 lactylation by 2.5-fold and promote the transcription of 169 metastasis-related genes. This cascade of events ultimately results in enhanced ALDOA-driven glycolysis and histone lactylation-mediated metastatic potential of non-CSC lung cancer cells. We have delineated a complex regulatory network utilized by CSCs to transfer their high metastatic activity to non-CSCs through exosomal Mir100hg, providing new mechanistic insights into the communication between these two heterogeneous tumor cell populations. These mechanistic insights provide novel therapeutic targets for metastatic lung cancer, including HNRNPF/HNRNPA2B1-mediated Mir100hg trafficking and the histone lactylation pathway, advancing our understanding of CSC-mediated metastasis while suggesting promising strategies for clinical intervention.

Copper oxide nanoparticles (CuONPs) have been widely applied, posing potential risks to human health. Although the toxicity of CuONPs on the liver and spleen has been reported, their effects on reproductive health remain unexplored. In this study, we investigate the effects of CuONPs on embryonic development and their potential mechanisms. Our results demonstrate that CuONPs exposure impairs mouse preimplantation embryonic development, particularly affecting the morula-to-blastocyst transition. Additionally, CuONPs were found to reduce the pluripotency of the inner cell mass (ICM) and mouse embryonic stem cells (mESCs). Mechanistically, CuONPs block autophagic flux and impair mitophagy, leading to the accumulation of damaged mitochondria. This mitochondrial dysfunction leads to reduced tricarboxylic acid (TCA) cycle activity and decreased α-ketoglutarate (α-KG) production. Insufficient α-KG induces the failure of DNA demethylation, reducing corresponding chromatin accessibility and consequently inhibiting ICM-specific genes expressions. Similar reduced development and inhibitions of pluripotency gene expression were observed in CuONPs-treated human blastocysts. Moreover, in women undergoing assisted reproductive technology (ART), a negative correlation was found between urinary Cu ion concentrations and clinical outcomes. Collectively, our study elucidates the mitophagy-mediated metabolic mechanisms of CuONPs embryotoxicity, improving our understanding of the potential reproductive toxicity associated with it.