Cancer Biology & Medicine最新文献

Colorectal cancer (CRC) is a common malignant tumor with a high mortality rate worldwide. Advanced CRC often leads to liver metastasis, which has a poor prognosis, highlighting the need to investigate the underlying mechanisms. Omics, encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics, enables comprehensive molecular analysis of cells and tissues. Tumor-omics research has advanced rapidly, with growing attention on CRC-related omics. However, systematic reviews on omics research specific to colorectal cancer liver metastasis (CRLM) are limited. This review summarizes the current status and progress of multi-omics research on CRLM and discusses the application of multi-omics technologies in basic research and the significant clinical implications.

Objective: Lung cancer is the leading cause of cancer-related deaths worldwide. Chemotherapy is associated with side effects, such as damage to myeloid cells and a reduction in the number of immune cells in patients. In addition, tumor cells hijack the mitochondria of immune cells through tunnel nanotubes, thereby weakening immune ability.

Methods: In this study the effects of direct mitochondria transplantation on cancer cell proliferation and chemotherapeutic sensitivity were determined, as well as anti-tumor immunity in in vitro and in vivo lung cancer models.

Results: A combination of mitochondrial transplantation and cisplatin chemotherapy was shown for the first time to significantly improve immune infiltration of advanced non-small cell lung cancer (NSCLC) and overcome the shortcomings of cisplatin chemotherapy, including damage to myeloid cells and a reduction in the number of immune cells.

Conclusions: The findings of the current study provide valuable recommendations for enhancing immune infiltration and augmenting anti-tumor efficacy during chemotherapy in advanced NSCLC. In addition, the findings support "mitochondrial transfer" as a novel paradigm in tumor treatment.

CD8⁺ T cell exhaustion, a critical challenge in the immune response to cancer, is characterized by a profound decline in the functionality of effector CD8⁺ T cells. This state of exhaustion is accompanied by the upregulation of various inhibitory receptors and significant shifts in both transcriptional and epigenetic profiles, thus ultimately leading to inadequate tumor control. Therapeutic strategies aimed at reversing CD8⁺ T cell exhaustion have the potential to rejuvenate immune responses and enhance treatment efficacy. This review compiles current knowledge regarding the molecular mechanisms underlying CD8⁺ T cell exhaustion, including the roles of immune checkpoint molecules, the tumor microenvironment, metabolic reprogramming, transcription factors, and epigenetic modifications. Emerging therapeutic approaches designed to combat CD8⁺ T cell exhaustion are evaluated, with emphasis on the modulation of immune checkpoints; targeting of metabolic and transcriptional changes; and exploration of other innovative strategies, such as epigenetic editing and engineered CAR-T cells. Importantly, we expand the exhaustion concept to immune cells beyond CD8⁺ T cells, such as CD4⁺ T cells, natural killer cells, and myeloid populations, thereby highlighting the broader implications of systemic immunosuppression in the cancer context. Finally, we propose avenues for future research aimed at further elucidating the factors and molecular mechanisms associated with CD8⁺ T cell exhaustion, thereby underscoring the critical need for strategies aimed at reversing this state to improve outcomes in cancer immunotherapy.

Objective: Migrasomes, an emerging class of migration-facilitating membranous extracellular vesicles, remain largely uncharted in the intricate landscape of tumor metastasis. This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis (BCBM).

Methods: Migrasomes were isolated and purified from BCBM cells (231-BR) and non-specific organotropic parental counterparts (MDA-MB-231), specifically designated as Mig-BCBM and Mig-BC, respectively. The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model. The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR, western blotting, immunofluorescence, ex vivo fluorescence imaging, and a series of rescue experiments.

Results: Mig-BCBM potently augmented the permeability of vascular endothelial layers, which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro. The administration of Mig-BCBM significantly disrupted the blood-brain barrier (BBB) and accelerated BCBM progression in vivo, as evidenced in mouse models, compared to the Mig-BC and control groups. Mechanistically, Mig-BCBM harbored ATF6, a critical transducer of endoplasmic reticulum (ER) stress. Upon internalization into hCMEC/D₃ cells, ATF6 elicited robust ER stress responses, culminating in downregulation of ZO-1 and VE-cadherin. Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals.

Conclusions: This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis, suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo.

Objective: Tumor-associated macrophages (TAMs) exhibit heterogeneous properties including anti-tumorigenic and pro-tumorigenic phenotypes. The rate-limiting enzyme in de novo serine biosynthesis, 3-phosphoglycerate dehydrogenase (PHGDH), has a well-established role in cellular metabolism, yet its specific role in macrophages remains unknown.

Methods: Metabolomics assays were conducted to assess metabolite composition and dynamics in macrophages. Changes in polarization and immunosuppressive markers were validated with qRT-PCR. Bioinformatics was used to analyze immune cell subsets and associated metabolic pathways. Finally, ChIP-qPCR and co-immunoprecipitation assays were performed to elucidate the downstream regulatory mechanisms of PHGDH.

Results: Serine metabolism was found to be downregulated in TAMs in breast cancer. Functional studies revealed that PHGDH inhibition promotes an M2-like phenotype and immunosuppressive functions in macrophages. Furthermore, PHGDH was found to undergo nuclear translocation during macrophage polarization. Mechanistically, nuclear PHGDH was found to regulate GLUD1 and GLS2 transcription via interaction with the transcription factor STAT3. Rescue experiments demonstrated that glutamine supplementation and STAT3 inhibition reversed the effects of PHGDH on macrophage function.

Conclusions: Our findings reveal a previously unrecognized non-canonical metabolic function of PHGDH, thus providing potential therapeutic targets in the tumor microenvironment for reversing malignant progression.