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Metastatic immunoediting in breast cancer cells

ABSTRACT: Metastatic immunoediting in breast cancer cells

PROVIDER: PRJNA1081861 | ENA |

REPOSITORIES: ENA

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Metastatic immunoediting in breast cancer cells

Project description:During the metastatic process, most of the disseminated tumor cells fail to adapt to new tissue conditions upon arrival and die, resulting in a selection of the fittest cells. Among these hurdles, the immune system’s anti-tumor activity is one of the main barriers of metastatic colonization. Among the different Metastasis-initiating cells (MICs) properties, immune evasion stands out as one of the most necessary traits leading metastasis. The immune landscape of distant organs impose immune pressure on tumor cells engaging a process of tumor-immune coevolution and selection of immune-evasive tumor cells, in a process called cancer immunoediting. In this study, we aimed to investigate the altered gene patterns of breast cancer cells induced by the interaction with the immune system. Specifically, we were looking for phenotypes and immune-evasive behaviour of immunoedited cells leading the metastatic colonization.

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DNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and in response to immunotherapy

Project description:Cancers evade the immune system in order to grow or metastasise through the process of cancer immunoediting. While checkpoint inhibitor therapy has been effective for reactivating tumour immunity in some cancers, many solid cancers, including breast cancer, remain largely non-responsive. Understanding the way non-responsive cancers evolve to evade immunity, what resistance pathways are activated and whether this occurs at the clonal level will improve immunotherapeutic design. We tracked cancer cell clones during the immunoediting process and determined clonal transcriptional profiles that allow immune evasion in murine mammary tumour growth in response to immunotherapy with anti-PD1 and anti-CTLA4. Clonal diversity was significantly restricted by immunotherapy treatment at both the primary and metastatic sites. These findings demonstrate that immunoediting selects for pre-existing breast cancer cell populations, that immunoediting is not a static process and is ongoing during metastasis and immunotherapy treatment. Isolation of immunotherapy resistant clones revealed unique and overlapping transcriptional signatures. The overlapping gene signature was predictive of poor survival in basal-like breast cancer patient cohorts. Some of these overlapping genes have existing small molecules which can be used to potentially improve immunotherapy response.

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Lactate uptake and oxidation via mitochondrial CD147/MCT1/LDHB complex contributes to stemness potentials in metastatic breast cancer

Project description:Metastatic cancer cells, originating from cancer stem cells with metastatic capacity, utilize nutrient flexibility to overcome the hurdles of metastatic cascade. However, the nutrient supply for maintaining the stemness potentials of metastatic cancer cells remains unknown. Here, we revealed that metastatic breast cancer cells maintain stemness and initiate metastasis upon detachment via uptaking and oxidating lactate. In detached metastasizing breast cancer cells, lactate was incorporated into tricarboxylic acid cycle and boosted oxidative phosphorylation, and then promoted the stemness potentials via α-KG-DNMT3B-mediated SOX2 hypomethylation. Moreover, lactate was uptake and oxidated in mitochondria by CD147/MCT1/LDHB complex, whose existence correlates to the stemness potentials and tumor metastasis in breast cancer patients. An intracellularly expressed single chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupted mitochondrial CD147/MCT1/LDHB complex, inhibited lactate-induced stemness potentials, depleted circulating breast cancer cells and reduced metastatic burden, suggesting a promising clinical application in reducing lactate-fueled metastasis.

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Project description:Aurora US Metastatic Breast Cancer Retrospective Project

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