Cancer Biology & Medicine最新文献

Pancreatic cancer (PC) is a highly aggressive cancer characterized by a unique tumor microenvironment (TME) that confers resistance to traditional therapies. As the dominant stromal cells in the TME, cancer-associated fibroblasts (CAFs) promote PC progression by modulating the extracellular matrix and interacting with surrounding cells. Numerous PC treatment strategies targeting CAFs have been explored in the past decade. However, targeting different subtypes of CAFs leads to varying therapeutic outcomes, highlighting the intricate and multifaceted nature of CAFs. The heterogeneity and dynamism of CAFs increase the complexity and challenges associated with tumor therapeutics. Currently, combination therapies incorporating CAF-targeted approaches in PC treatment have shown encouraging outcomes in select clinical trials. A comprehensive understanding of CAFs is essential for developing individualized therapeutic approaches. This review outlines the current knowledge of CAF heterogeneity, crosstalk with surrounding cells, and strategies for targeting CAFs in PC, aiming to keep researchers and clinicians up-to-date with the latest information on CAFs in PC.

Breast cancer mortality is driven predominantly by metastasis, which affects 20-30% of patients with early-stage disease despite guideline-directed therapies. Because conventional imaging modalities currently lack sensitivity to identify residual disease, molecular-level monitoring must be developed. Circulating tumor DNA (ctDNA) profiling currently enables transformative minimal residual disease (MRD) detection and can quantify tumor burden at low variant allele frequencies. This review provides a comprehensive overview of MRD in breast cancer, including its definition, detection technologies, positivity thresholds, pathophysiology, clinical applications in adjuvant and neoadjuvant settings, ongoing clinical trials, challenges, and future directions. ctDNA-defined MRD has potential as a precision tool for adaptive therapy, and might facilitate post-adjuvant interception, whereby targeted therapies are administered to eradicate micro-metastases before radiographic recurrence. Persistent challenges include MRD assay standardization, subtype-specific MRD thresholds, tumor heterogeneity, and positioning MRD as a potentially valuable tool for precision management in breast cancer.

Primary cilia, microtubule-based organelles protruding from the surfaces of most eukaryotic cells, have critical roles in maintaining cellular homeostasis, by sensing, transducing, and transmitting diverse extracellular and intracellular signals through multiple signaling pathways, including the Hedgehog, Notch, and Wnt pathways. Consequently, structural or functional abnormalities in primary cilia often lead to various human diseases, including cancer. Although primary cilia are frequently absent in most cancer types, they paradoxically facilitate tumor initiation and progression in certain malignancies. Therefore, elucidating the complex interplay between primary cilia and cancer might provide novel insights for cancer treatment. In this review, we summarize current insights into the structure and function of primary cilia, explore their roles in key tumor-associated signaling pathways, and discuss emerging evidence linking ciliary dysfunction to cancer development and progression. We also highlight recent advances in targeting cilia-associated mechanisms as potential therapeutic strategies in oncology.

Objective: Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy. Nintedanib, a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tumors, has yet to be investigated in combination with radiotherapy. This study aimed to evaluate the antitumor efficacy of nintedanib in conjunction with radiotherapy.

Methods: Tumor-bearing models were utilized to assess the antitumor effects and safety of treatment with nintedanib and radiotherapy in vivo. Reactive oxygen species (ROS), lipid peroxidation assays, and transmission electron microscopy were used to determine the impact of the combined treatment strategy on tumor cell death. Overexpression plasmids and shRNA knockdown techniques were applied to explore and validate the underlying mechanisms.

Results: The combination of nintedanib and radiotherapy demonstrated a potent antitumor effect in vivo. Nintedanib suppressed the SLC7A11-mediated GSH synthesis pathway by downregulating ATF4, the expression of which was elevated in response to radiation as an adaptive mechanism. Consequently, nintedanib combined with radiotherapy enhanced ferroptosis in tumor cells.

Conclusions: These findings support the use of nintedanib in combination with radiotherapy as an effective, low-toxicity treatment strategy, highlighting the antitumor potential of ATF4-targeted agents.

Melanoma, the most aggressive form of skin cancer, remains a significant clinical challenge due to the high metastatic potential and drug resistance. This review explores the pivotal roles of angiogenesis and vasculogenic mimicry in melanoma progression and treatment resistance. Angiogenesis, driven primarily by VEGF/VEGFR signaling, is critical for tumor sustenance but is often insufficient under hypoxic conditions, prompting melanoma cells to adapt by forming vascular-like structures (i.e., vasculogenic mimicry). These structures enable melanoma cells to mimic endothelial functions and are linked to increased metastasis and poor prognosis. Molecular drivers, including VE-cadherin, EphA2, and hypoxia-inducible factors, have been identified as key regulators of these processes. Current anti-angiogenic agents have limited efficacy in advanced/metastatic melanoma due to tumor plasticity and the interplay between angiogenesis and vasculogenic mimicry. The review highlights the need for therapeutic strategies targeting both mechanisms, emphasizing the importance of combination treatments to overcome resistance. Future research should aim to elucidate the molecular underpinnings of angiogenesis and vasculogenic mimicry to improve melanoma management and patient outcomes.

Objective: This study aimed at exploring the effects of the epigenetic regulator, chidamide, on reprogramming the immunosuppressive tumor microenvironment in small cell lung cancer (SCLC), particularly the roles in macrophage polarization and angiogenesis. The therapeutic efficacy of combining chidamide with the anti-angiogenic agent, anlotinib, for refractory SCLC was also evaluated.

Methods: RNA sequencing and functional validation were performed to assess chidamide's effects on macrophages. Signal transducer and activator of transcription 4 (STAT4)-mediated transcriptional activation of CCL2 was confirmed with ChIP-qPCR. The synergistic efficacy of chidamide in combination with anlotinib was tested in preclinical models.

Results: Chidamide enhanced macrophage infiltration and induced macrophage polarization toward the anti-tumor M1 phenotype. Mechanistically, chidamide upregulated CCL2 via STAT4 transcriptional activation, thereby reshaping the tumor immune microenvironment (TIME). Combining chidamide with anlotinib synergistically suppressed tumor growth and remodeled the immunosuppressive TME in SCLC in vivo.

Conclusions: Chidamide reshaped the SCLC TIME by activating STAT4/CCL2, thus driving M1 macrophage polarization and enhancing anti-tumor immunity. Our findings highlight coordinated TIME-targeted therapy as a translatable strategy to overcome therapeutic resistance in SCLC and provide a rationale for clinical trials examining epigenetic and anti-angiogenic therapeutics combinations.

Objective: Large-scale CRISPR screens have identified essential genes across cancer cell lines, but links between tumor functional properties and specific dependencies require investigation to reveal the mechanisms underlying dependencies and broaden understanding of targeted therapy.

Methods: We selected 47 breast cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) with multi-omics data including gene dependency; somatic mutations; copy number alterations; and transcriptomic, proteomic, metabolomic, and methylation data. We established a dependency marker association (DMA) analytic pipeline by using linear regression modeling to assess associations between 3,874 representative gene dependencies and multi-omics markers. Additionally, we conducted non-negative matrix factorization clustering, to stratify breast cancer cell lines according to gene dependency features, and investigated cluster-specific DMAs.

Results: We interpreted valuable DMAs according to two primary aspects. First, dependencies associated with gain-of-function alterations revealed addiction to lactate transporter SLC16A3, thus suggesting a promising therapeutic target. Second, dependencies associated with loss-of-function alterations included synthetic lethality (SL), collateral SL, and prioritized metabolic SL, encompassing paralog SL (e.g., IMPDH1 and IMPDH2), single pathway SL (e.g., GFPT1 and UAP1), and alternative pathway SL (e.g., GPI and PGD). DMA analysis of the two clusters with divergent dependency signatures demonstrated that cluster1 cell lines exhibited extensive metabolism with mitochondrial protein dependencies, whereas cluster2 displays enhanced cell signaling, and reliance on DNA replication and membrane organelle regulators.

Conclusions: We established a DMA analysis pipeline linking the gene dependencies of breast cancer cell lines to multi-omics characteristics, thus elucidating the underpinnings of tumor dependencies and offering a valuable resource for developing novel precision treatment strategies incorporating relevant markers.