Similar Datasets
Project description:Tumour-induced systemic accumulation and polarisation of neutrophils to an immunosuppressive phenotype is a potent driver of metastasis formation. Yet how mammary tumours reprogram granulopoiesis at the molecular level and when tumour imprinting occurs during neutrophil development remains underexplored. Here we combined single cell, chromatin and functional analyses to unravel the tumour-driven reprogramming of granulopoiesis, along with intervention studies aimed at reversing this process. We observe that mammary tumours accelerate commitment to the neutrophil lineage at the expense of lymphopoiesis and erythropoiesis without stimulating the development of a novel myeloid lineage. Moreover, tumour-directed immunosuppressive imprinting of neutrophils starts early in haematopoiesis. Treatment with anti-IL-1β normalised tumour-induced granulopoiesis, reduced neutrophil production of T cell suppressive superoxides and mitigated metastatic spread. Together, these data provide molecular insights into the aberrant tumour-driven neutrophil differentiation pathway leading to metastasis-promoting chronic inflammation and how it can be reversed to reduce metastatic spread.
2025-04-08 | GSE264087 | GEO
Project description:Tumour-induced systemic accumulation and polarisation of neutrophils to an immunosuppressive phenotype is a potent driver of metastasis formation. Yet how mammary tumours reprogram granulopoiesis at the molecular level and when tumour imprinting occurs during neutrophil development remains underexplored. Here we combined single cell, chromatin and functional analyses to unravel the tumour-driven reprogramming of granulopoiesis, along with intervention studies aimed at reversing this process. We observe that mammary tumours accelerate commitment to the neutrophil lineage at the expense of lymphopoiesis and erythropoiesis without stimulating the development of a novel myeloid lineage. Moreover, tumour-directed immunosuppressive imprinting of neutrophils starts early in haematopoiesis. Treatment with anti-IL-1β normalised tumour-induced granulopoiesis, reduced neutrophil production of T cell suppressive superoxides and mitigated metastatic spread. Together, these data provide molecular insights into the aberrant tumour-driven neutrophil differentiation pathway leading to metastasis-promoting chronic inflammation and how it can be reversed to reduce metastatic spread.
2025-04-08 | GSE264085 | GEO
Project description:Tumour-induced systemic accumulation and polarisation of neutrophils to an immunosuppressive phenotype is a potent driver of metastasis formation. Yet how mammary tumours reprogram granulopoiesis at the molecular level and when tumour imprinting occurs during neutrophil development remains underexplored. Here we combined single cell, chromatin and functional analyses to unravel the tumour-driven reprogramming of granulopoiesis, along with intervention studies aimed at reversing this process. We observe that mammary tumours accelerate commitment to the neutrophil lineage at the expense of lymphopoiesis and erythropoiesis without stimulating the development of a novel myeloid lineage. Moreover, tumour-directed immunosuppressive imprinting of neutrophils starts early in haematopoiesis. Treatment with anti-IL-1β normalised tumour-induced granulopoiesis, reduced neutrophil production of T cell suppressive superoxides and mitigated metastatic spread. Together, these data provide molecular insights into the aberrant tumour-driven neutrophil differentiation pathway leading to metastasis-promoting chronic inflammation and how it can be reversed to reduce metastatic spread.
2025-04-08 | GSE264086 | GEO
Project description:Understanding and reversing mammary tumour-driven reprogramming of myelopoieisis to reduce metastatic spread
| PRJNA1100962 | ENA
Project description:Understanding and reversing mammary tumour-driven reprogramming of myelopoieisis to reduce metastatic spread [scRNA-seq]
| PRJNA1100977 | ENA
Project description:Understanding and reversing mammary tumour-driven reprogramming of myelopoieisis to reduce metastatic spread [ATAC-seq]
| PRJNA1100963 | ENA
Project description:Understanding and reversing mammary tumour-driven reprogramming of myelopoieisis to reduce metastatic spread [bulk RNA-seq]
| PRJNA1100970 | ENA
Project description:Little is known about the role of Sox11 in the regulation of mammary progenitor cells. Sox11 is expressed by mammary bud epithelial cells during embryonic mammary gland development and is not detected in mammary epithelial cells after birth. As Sox11 is an oncofetal gene, we investigated the effects of reducing Sox11 levels in embryonic mammary progenitor cells and found that Sox11 regulates proliferative state, stem cell activity and lineage marker expression. We also investigated the effect of reducing Sox11 levels in two transplantable Brca1-deficient oestrogen receptor-negative mouse mammary tumour cell lines, to assess whether Sox11 regulates similar functions in tumour progenitor cells. When Sox11 levels were reduced in one Brca1-deficient mammary tumour cell line that expressed both epithelial and mesenchymal markers, similar effects on proliferation, stem cell activity and expression of lineage markers to those seen in the embryonic mammary progenitor cells were observed. Orthotopic grafting of mammary tumour cells with reduced Sox11 levels led to alterations in tumour-initiating capacity, latency, expression of lineage markers and metastatic burden. Our results support a model in which tumours expressing higher levels of Sox11 have more stem and tumour-initiating cells, and are less proliferative, whereas tumours expressing lower levels of Sox11 become more proliferative and capable of morphogenetic/metastatic growth, similar to what occurs during embryonic mammary developmental progression.
| S-EPMC8188883 | biostudies-literature
Project description:The role of lymph node metastases in distant prostate cancer dissemination and lethality is ill defined. Patients with metastases restricted to lymph nodes have a better prognosis than those with distant metastatic spread, suggesting the possibility of distinct aetiologies. To explore this, we traced patterns of cancer dissemination using tumour phylogenies inferred from genome-wide copy-number profiling of 48 samples across 3 patients with lymph node metastatic disease and 3 patients with osseous metastatic disease. Our results show that metastatic cells in regional lymph nodes originate from evolutionary advanced extraprostatic tumour cells rather than less advanced central tumour cell populations. In contrast, osseous metastases do not exhibit such a constrained developmental lineage, arising from either intra or extraprostatic tumour cell populations, at early and late stages in the evolution of the primary. Collectively, this comparison suggests that lymph node metastases may not be an intermediate developmental step for distant osseous metastases, but rather represent a distinct metastatic lineage.
| S-EPMC5031992 | biostudies-literature
Project description:BackgroundThe receptor encoded by the MET oncogene and its ligand Hepatocyte Growth Factor (HGF) are at the core of the invasive-metastatic behavior. In a number of instances genetic alterations result in ligand-independent onset of malignancy (MET addiction). More frequently, ligand stimulation of wild-type MET contributes to progression toward metastasis (MET expedience). Thus, while MET inhibitors alone are effective in the first case, combination therapy with ligand inhibitors is required in the second condition.MethodsIn this paper, we generated hybrid molecules gathering HGF and MET inhibitory properties. This has been achieved by 'head-to-tail' or 'tail-to-head' fusion of a single chain Fab derived from the DN30 MET antibody with a recombinant 'ad-hoc' engineered MET extracellular domain (decoyMET), encompassing the HGF binding site but lacking the DN30 epitope.ResultsThe hybrid molecules correctly bind MET and HGF, inhibit HGF-induced MET downstream signaling, and quench HGF-driven biological responses, such as growth, motility and invasion, in cancer cells of different origin. Two metastatic models were generated in mice knocked-in by the human HGF gene: (i) orthotopic transplantation of pancreatic cancer cells; (ii) subcutaneous injection of primary cells derived from a cancer of unknown primary. Treatment with hybrid molecules strongly affects time of onset, number, and size of metastatic lesions.ConclusionThese results provide a strategy to treat metastatic dissemination driven by the HGF/MET axis.
| S-EPMC7807714 | biostudies-literature