Modulating Immune Cells to Prevent Breast Cancer Lung Metastasis
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ABSTRACT:
PROVIDER: PRJNA436027 | ENA |
REPOSITORIES: ENA
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Project description:Current lack of insight into mechanisms governing breast cancer metastasis has precluded development of curative therapies. Metastasis-initiating cells (MICs) are cancer cells uniquely equipped to establish metastatic outgrowths and are thought to cause recurrence and therapeutic resistance. Using various models of early metastatic disease, we have uncovered mechanisms by which certain primary tumors can prevent MICs from generating secondary tumors. In such cases, the primary tumor elicits a systemic immune response involving IL-1β expressing innate inflammatory cells that infiltrate the distant MIC microenvironment. Elevated IL-1β levels at the metastatic site prevent MICs from generating their highly proliferative E-cadherin-positive epithelial progeny. Thus, when the inherent plasticity of MICs is impeded, robustly growing tumors cannot be established. Ablation of the pro-inflammatory response or IL-1R inhibition relieves the block in differentiation and results in MIC colonization. Our data reveal complex and potentially life-prolonging interactions that occur between primary tumors and disseminated MICs that could be exploited to improve survival of patients at risk for metastatic disease.
2018-06-26 | GSE111157 | GEO
Project description:Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Breast Cancer Bone Metastasis
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Project description:The presence of disseminated tumor cells in patient bone marrow (BM) aspirates predicts decreased recurrence-free survival, yet little is known about whether hematopoietic BM cells impact bone metastases. Here, we report that the BM can be rendered metastasis-suppressive by the bone-targeting bisphosphonate, zoledronic acid (ZA). In particular, ZA modulates hematopoietic myeloid/osteoclast progenitor cell (M/OCP) lineage potential to render them metastasis-suppressive. Granulocyte-colony stimulating factor (G-CSF) promotes resistance to ZA by re-directing M/OCP differentiation. We identified BM transcriptional programs that associate with metastasis suppression and resistance to ZA. Analysis of patient blood samples taken at randomization revealed that women with plasma G-CSF levels >23 pg/mL experienced significantly worse outcome with adjuvant ZA than those on ZA who had lower plasma G-CSF levels. Our findings establish that hematopoietic cells and M/OCP lineage potential profoundly impact bone metastasis and support the discovery of biomarkers that stratify therapeutic responses in patients at risk of recurrence.
2021-02-25 | GSE108250 | GEO
Project description:Cancer vaccines, reassembled from whole tumor tissue components, were applied to demonstrate the across-cancer immune responses, thanks to inducing pan-clones T cells immune responses. It is demonstrated that across-cancer immune responses among different types of cancers exist and can be induced by nanovaccines or microvaccines, which thus can prevent different types of cancers and cancer metastasis. In addition, ths study revealed that such across-cancer immune responses among different types of cancers is induced by the fact that many neoantigens are shared by different types of cancer cells.
2022-10-24 | PXD037688 | iProX
Project description:Non-immune niche analysis in breast tumour derived lung metastasis
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Project description:Abstract:
Accumulating experimental and clinical evidence suggest that the immune response to cancer is not exclusively anti-tumor. Indeed, the pro-tumor roles of the immune system - as suppliers of growth and pro-angiogenic factors or defenses against cytotoxic immune attacks, for example - have been long appreciated, but relatively few theoretical works have considered their effects. Inspired by the recently proposed "immune-mediated" theory of metastasis, we develop a mathematical model for tumor-immune interactions at two anatomically distant sites, which includes both anti- and pro-tumor immune effects, and the experimentally observed tumor-induced phenotypic plasticity of immune cells (tumor "education" of the immune cells). Upon confrontation of our model to experimental data, we use it to evaluate the implications of the immune-mediated theory of metastasis. We find that tumor education of immune cells may explain the relatively poor performance of immunotherapies, and that many metastatic phenomena, including metastatic blow-up, dormancy, and metastasis to sites of injury, can be explained by the immune-mediated theory of metastasis. Our results suggest that further work is warranted to fully elucidate the pro-tumor effects of the immune system in metastatic cancer.
2024-09-02 | BIOMD0000000926 | BioModels
Project description:Estrogen receptor (ER)-positive luminal breast cancer is a subtype with generally lower risk of metastasis to most distant organs. However, bone recurrence occurs preferentially in luminal cancer. The mechanisms of the subtype-specific organotropism remain elusive. Here we show that an ER-regulated secretory protein SCUBE2 contributes to bone tropism of luminal breast cancer. Single-cell RNA sequencing analysis reveals osteoblastic enrichment by SCUBE2 in early bone-metastatic niches. SCUBE2 facilitates release of tumor membrane-anchored SHH to activate Hedgehog signaling in mesenchymal stem cells, thus promoting osteoblast differentiation. Osteoblasts deposit collagens to suppress NK cells via the inhibitory LAIR1 signaling and promote tumor colonization. SCUBE2 expression and secretion are associated with osteoblast differentiation and bone metastasis in human tumors. Targeting Hedgehog by Sonidegib and targeting SCUBE2 with a neutralizing antibody both effectively suppress bone metastasis in multiple metastasis models. Overall, our findings provides an explanation for bone preference in luminal breast cancer and new approaches for metastasis treatment.
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Project description:We used our novel Cherry-niche system to specifically isolate cells from the metastatic niche of 4T1 lung metastasis and compared their profile with the one obtained isolating lungs cells distal from the tumour growth.
2019-09-06 | GSE131508 | GEO