Core Insights - A new study from Tsukuba University reveals key molecular pathways regulating immune response and cancer metastasis in triple-negative breast cancer (TNBC) patients, potentially leading to innovative treatment options for this aggressive cancer type [1][2] Group 1: Research Findings - Researchers identified a transmembrane glycoprotein named "non-metastatic melanoma glycoprotein B" that is significantly elevated in TNBC tumor cells, with distinct molecular modification characteristics compared to other cells [1] - The identified glycoprotein promotes the differentiation of upstream cells into tumor-associated macrophages (TAMs), which enhance their immunosuppressive properties [1] - TAMs play a crucial role in tumor progression, invasion, metastasis, and treatment resistance by helping tumor cells evade immune attacks [1] Group 2: Implications for Treatment - Targeting the identified molecular pathway may lead to the development of new immunotherapies, drugs, and combination strategies with existing immune checkpoint blockade therapies, providing innovative treatment options for TNBC and other poor-prognosis cancers [2]

Core Viewpoint - The article discusses a groundbreaking study on breast cancer that introduces a high-throughput, high-genomic-resolution single-cell DNA and RNA multi-omics technology called wellDR-seq, which helps decode the origins and progression mechanisms of breast cancer [3][5][9]. Group 1 - The research team, led by Nicholas Navin at the MD Anderson Cancer Center, published their findings in the journal Cell, highlighting the first application of wellDR-seq technology [3][5]. - The study analyzed 33,646 single cells from 12 estrogen receptor-positive (ER+) breast cancer patients, identifying cancer ancestral subclones that may represent the origin cells of breast cancer [5][9]. - wellDR-seq allows for the study of gene dosage relationships at the subclonal level, revealing a near-linear correlation in large chromosomal regions and extensive variation at the single-gene level [6][9]. Group 2 - The research identified that 56% of copy number variation segments showed a near-linear correlation with gene expression, providing insights into the complex relationship between copy number and gene expression at the single-cell level [9]. - The study also identified dosage-sensitive and dosage-insensitive genes, including many breast cancer-related genes and incidental copy number variations in non-cancer cells [6][9]. - wellDR-seq is a versatile method applicable not only to breast cancer but also to other cancers and various biomedical fields, enhancing the understanding of cancer development [9].

Core Viewpoint - The research reveals that cancer cells hijack iron-rich macrophages in the bone marrow to promote bone metastasis and anemia, opening new avenues for therapies to mitigate both bone metastasis and associated severe anemia [3][12]. Group 1: Mechanism of Cancer Metastasis - Cancer cells effectively "hijack" a specific type of macrophage, known as VCAM1+ CD163+ CCR3+ macrophages, which are responsible for recycling iron in the bone, depriving red blood cells of the iron needed for maturation [5][10]. - The study indicates that the hijacking of these macrophages not only leads to a lack of iron necessary for red blood cell development but also supports tumor growth in the bone [9][10]. Group 2: Implications for Anemia - The cancer cells' action results in the red blood cells being in an immature state, leading to anemia due to insufficient healthy red blood cell production [9][10]. - Tumor cells simulate red blood cells to adapt to the hypoxic environment of the bone tissue, utilizing the stolen iron to produce hemoglobin, which is crucial for oxygen transport [9][12]. Group 3: Research Significance - This research shifts the focus from solely studying cancer cells ("seeds") to understanding the surrounding microenvironment ("soil") that facilitates cancer metastasis [7][8]. - The findings have broader implications beyond metastatic breast cancer, potentially extending to other major cancer types, highlighting the importance of the tumor's manipulation of its environment [12].

染色体外 DNA （ecDNA） 与 肿瘤 之间的关联已被充分证实，其在不同癌症中的作用愈发引人关注。然 而，尽管 ecDNA 被认为源于基因组不稳定性，但驱动 ecDNA 形成过程中 DNA 末端连接的分子机制，以 及控制其选择性基因包装的调控因素仍待阐明。 2025 年 8 月 21 日，南开大学药学院 孙涛 教授、 张恒 博士及 天津医科大学肿瘤医院 黄鼎智 医生等， 在 Cell 子刊 Molecular Cell 上发表了题为： Extrachromosomal DNA biogenesis is dependent on DNA looping and religation by YY1-Lig3-PARylation complex 的研究论文，该论文被选为当期封面论文。 该研究表明， 染色体外 DNA （ecDNA） 的生物发生依赖于由 YY1-Lig3-PARylation 复合物介导的 DNA 环化和重新连接，从而提出了 补充现有理论的 ecDNA 生物发生新模型。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 期刊封面：在一片生机勃勃的森林中潜藏着隐秘的危险——象征着 YY1-Lig3-PAR ...

Core Viewpoint - The study reveals that tumor-antigen-specific cytotoxic CD8+ T cells can be deployed remotely to inhibit lung metastasis of breast cancer, highlighting the importance of effector immune cell deployment in cancer treatment [3][8][11]. Group 1: Research Findings - The abundance of tumor-specific CD103+ CD8+ T cells in tumor-draining lymph nodes (TDLN) is associated with prolonged disease-free survival in breast cancer patients [8]. - CD103+ CD8+ T cells are activated in TDLN and recruited to the lungs via CCL25/CCR9 signaling, effectively suppressing tumor metastasis [8][9]. - Tumor-derived extracellular vesicles (EVs) polarize alveolar macrophages, leading to the release of CCL25 and IDO1, which can inhibit the deployment of CD103+ CD8+ T cells and promote lung metastasis [8][9]. Group 2: Implications for Cancer Treatment - Enhancing the recruitment of CD103+ CD8+ T cells or blocking IDO1 can potentially curb lung metastasis of tumors [9]. - The study emphasizes the adaptive immune system's capability to deploy remotely to protect distant organs from tumor metastasis, suggesting a potential therapeutic strategy in cancer treatment [11].

Core Viewpoint - The study reveals that the decline in leptin levels with age contributes to the accumulation of senescent CD8+ T cells in the tumor microenvironment, leading to weakened anti-tumor effects. Regulating leptin levels may be a promising therapeutic strategy for elderly cancer patients [3][7][10]. Group 1: Aging and T Cell Dysfunction - Aging is a major risk factor for various cancers, with patients aged 65 and above accounting for 60% of new cancer diagnoses [5]. - T cell immune remodeling due to aging results in poor clinical outcomes for cancer patients, as T cells lose physiological functions over time [5]. - Age-related changes in T cells and the impact of systemic metabolic alterations on T cell function and phenotype require further investigation [5]. Group 2: Role of Leptin - Leptin, produced by adipose tissue, informs the brain about the body's fat storage levels, with higher fat leading to increased leptin production [6]. - The study found that decreased leptin levels with age accelerate CD8+ T cell senescence, impairing T cell function in the tumor microenvironment [7][8]. - In human cancer patients, plasma leptin levels are negatively correlated with the degree of CD8+ T cell senescence within tumors [7][8]. Group 3: Implications for Treatment - The findings suggest that enhancing plasma leptin levels through the regulation of adipocyte metabolism may help prevent T cell senescence and improve anti-tumor immunity in elderly patients [10]. - Supplementing leptin could have therapeutic potential for elderly cancer patients [10].

Core Viewpoint - The study highlights the dynamic changes in the tumor microenvironment (TME) across various cancer types and stages, emphasizing the importance of understanding cellular interactions within the TME as a promising therapeutic target [3][7]. Group 1: Research Overview - The research published in Nature Cancer integrates data from 36 cancer types and 746 samples, analyzing over 4 million single cells and spatial transcriptomics data from 6 cancer types [4][5]. - A comprehensive atlas of TME heterogeneity, named TabulaTIME, was established, detailing six major cell lineages and 56 cell subtypes within the TME [7][9]. Group 2: Key Findings - The study identified CTHRC1 as a marker for cancer-associated fibroblasts (CAFs) that are enriched in various cancer types, indicating their role in immune cell infiltration prevention [9]. - The research demonstrated that TabulaTIME can be utilized for analyzing tumor ecotype composition and serves as a reference for cell type annotation, providing insights into potential therapeutic strategies targeting profibrotic ecotypes [9].

Core Viewpoint - Colorectal cancer (CRC) is the third most common cancer globally, with nearly 2 million new cases annually, and the second leading cause of cancer-related deaths, claiming nearly 1 million lives each year. The study published by Wuhan University researchers identifies a significant single nucleotide mutation (rs10871066) associated with increased risk of precancerous lesions and colorectal cancer, revealing underlying oncogenic mechanisms [2][5]. Group 1 - The research utilized multi-omics data from 533 colorectal tissue samples, ranging from normal tissues to early adenomas and cancers, to establish a dynamic epigenetic map [5]. - A total of 7,492 differential cis-regulatory elements (CREs) were identified, linked to 5,490 target genes [5]. - High-throughput CRISPR interference (CRISPRi) screening revealed 265 functional CREs associated with colorectal cancer cell proliferation [5]. Group 2 - A polygenic risk score (PRS) model based on functional CRE mutations effectively predicted colorectal cancer and precancerous lesions in 476,770 individuals [5]. - The functional mutation rs10871066 is significantly correlated with increased risk of precancerous lesions and colorectal cancer [5]. - Mechanistically, rs10871066 mediates the conversion from silencers to enhancers through FOXP1 and TCF7L2, leading to the upregulation of KLF5 and activation of oncogenic pathways, while also upregulating PIBF1 to inhibit natural killer (NK) cell cytotoxicity [5].

Core Viewpoint - The article discusses the role of SARM1 in axonal degeneration and its activation mechanism, highlighting its significance in neurodegenerative diseases and potential therapeutic strategies [2][7]. Group 1: Mechanism of SARM1 Activation - SARM1 is a key executor of axonal degeneration, activated through its TIR domain's NADase activity, leading to NAD⁺ depletion [2]. - The activation process involves NMN initiating SARM1's base exchange activity, forming covalent adducts with ADP-ribose, which promotes the assembly of superhelical SARM1 filaments [5]. - These filaments eventually coalesce into stable phase-separated assemblies with full enzymatic activity upon reaching a solubility limit [5]. Group 2: Implications for Therapeutic Strategies - The findings reveal a molecular mechanism that confines SARM1 activation to damaged axons, providing new insights for developing neuroprotective strategies targeting SARM1 [7]. - Interestingly, several clinical-stage inhibitors targeting the SARM1 TIR domain paradoxically promote its activation by forming similar adducts [6].

Core Viewpoint - The interaction between the brain and tumors is a critical yet underexplored aspect of cancer biology, with evidence suggesting that psychological stress significantly influences tumor development and treatment response [2][4]. Group 1 - A large meta-analysis involving 2,611,907 participants found a strong correlation between depression and anxiety with increased cancer incidence, cancer-specific mortality, and all-cause mortality [2]. - The brain regulates tumor occurrence and development through various neuroendocrine and neural pathways, including the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system, although the exact mechanisms remain largely unclear [2][4]. Group 2 - A recent study published in Nature Cancer revealed that colorectal cancer cells hijack a brain-gut polysynaptic circuit from the lateral septum to enteric neurons to sustain tumor growth [3][4]. - The study identified that GABAergic neurons in the lateral septum connect with cholinergic neurons in the gut, which extend to the tumor microenvironment (TME), and these neurons are exploited by colorectal cancer cells to promote tumor growth [7]. - Chronic stress in a mouse model enhances the activity of this circuit, exacerbating tumor progression, and clinical observations indicate that increased neuronal activity in the lateral septum correlates with larger primary tumors in colorectal cancer patients [7][9].