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1.
Cancer Discov ; 14(7): 1252-1275, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38427556

ABSTRACT

Bone is the most common site of breast cancer metastasis. Bone metastasis is incurable and is associated with severe morbidity. Utilizing an immunocompetent mouse model of spontaneous breast cancer bone metastasis, we profiled the immune transcriptome of bone metastatic lesions and peripheral bone marrow at distinct metastatic stages, revealing dynamic changes during the metastatic process. We show that cross-talk between granulocytes and T cells is central to shaping an immunosuppressive microenvironment. Specifically, we identified the PD-1 and TIGIT signaling axes and the proinflammatory cytokine IL1ß as central players in the interactions between granulocytes and T cells. Targeting these pathways in vivo resulted in attenuated bone metastasis and improved survival, by reactivating antitumor immunity. Analysis of patient samples revealed that TIGIT and IL1ß are prominent in human bone metastasis. Our findings suggest that cotargeting immunosuppressive granulocytes and dysfunctional T cells may be a promising novel therapeutic strategy to inhibit bone metastasis. Significance: Temporal transcriptome profiling of the immune microenvironment in breast cancer bone metastasis revealed key communication pathways between dysfunctional T cells and myeloid derived suppressor cells. Cotargeting of TIGIT and IL1ß inhibited bone metastasis and improved survival. Validation in patient data implicated these targets as a novel promising approach to treat human bone metastasis.


Subject(s)
Bone Neoplasms , Breast Neoplasms , Myeloid-Derived Suppressor Cells , Receptors, Immunologic , Animals , Mice , Female , Bone Neoplasms/secondary , Bone Neoplasms/immunology , Breast Neoplasms/pathology , Breast Neoplasms/immunology , Breast Neoplasms/drug therapy , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Humans , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/metabolism , Tumor Microenvironment/immunology
2.
Trends Cancer ; 10(3): 208-229, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38072691

ABSTRACT

The tumor microenvironment (TME) is an integral part of tumors and plays a central role in all stages of carcinogenesis and progression. Each organ has a unique and heterogeneous microenvironment, which affects the ability of disseminated cells to grow in the new and sometimes hostile metastatic niche. Resident stromal cells, such as fibroblasts, osteoblasts, and astrocytes, are essential culprits in the modulation of metastatic progression: they transition from being sentinels of tissue integrity to being dysfunctional perpetrators that support metastatic outgrowth. Therefore, better understanding of the complexity of their reciprocal interactions with cancer cells and with other components of the TME is essential to enable the design of novel therapeutic approaches to prevent metastatic relapse.


Subject(s)
Neoplasm Recurrence, Local , Stromal Cells , Humans , Neoplasm Recurrence, Local/pathology , Stromal Cells/pathology , Carcinogenesis/pathology , Fibroblasts , Tumor Microenvironment
3.
Nat Cancer ; 4(3): 401-418, 2023 03.
Article in English | MEDLINE | ID: mdl-36797502

ABSTRACT

Brain metastasis still encompass very grim prognosis and therefore understanding the underlying mechanisms is an urgent need toward developing better therapeutic strategies. We uncover the intricate interactions between recruited innate immune cells and resident astrocytes in the brain metastatic niche that facilitate metastasis of melanoma and breast cancer. We show that granulocyte-derived lipocalin-2 (LCN2) induces inflammatory activation of astrocytes, leading to myeloid cell recruitment to the brain. LCN2 is central to inducing neuroinflammation as its genetic targeting or bone-marrow transplantation from LCN2-/- mice was sufficient to attenuate neuroinflammation and inhibit brain metastasis. Moreover, high LCN2 levels in patient blood and brain metastases in multiple cancer types were strongly associated with disease progression and poor survival. Our findings uncover a previously unknown mechanism, establishing a central role for the reciprocal interactions between granulocytes and astrocytes in promoting brain metastasis and implicate LCN2 as a prognostic marker and potential therapeutic target.


Subject(s)
Astrocytes , Brain Neoplasms , Mice , Animals , Lipocalin-2/genetics , Lipocalin-2/metabolism , Astrocytes/metabolism , Neuroinflammatory Diseases , Brain Neoplasms/genetics , Immunity, Innate
4.
Nat Commun ; 13(1): 5797, 2022 10 02.
Article in English | MEDLINE | ID: mdl-36184683

ABSTRACT

Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an urgent challenge. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. Here we show that systemic treatment with doxorubicin, but not cisplatin, following resection of a triple-negative breast tumor induces the expression of complement factors in lung fibroblasts and modulates an immunosuppressive metastatic niche that supports lung metastasis. Complement signaling derived from cancer-associated fibroblasts (CAFs) mediates the recruitment of myeloid-derived suppressor cells (MDSCs) to the metastatic niche, thus promoting T cell dysfunction. Pharmacological targeting of complement signaling in combination with chemotherapy alleviates immune dysregulation and attenuates lung metastasis. Our findings suggest that combining cytotoxic treatment with blockade of complement signaling in triple-negative breast cancer patients may attenuate the adverse effects of chemotherapy, thus offering a promising approach for clinical use.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Lung Neoplasms , Triple Negative Breast Neoplasms , Antineoplastic Agents/pharmacology , Breast Neoplasms/pathology , Cell Line, Tumor , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Female , Humans , Immunosuppression Therapy , Lung Neoplasms/pathology , Neoplasm Recurrence, Local/drug therapy , Triple Negative Breast Neoplasms/pathology
5.
Sci Rep ; 10(1): 13838, 2020 08 14.
Article in English | MEDLINE | ID: mdl-32796899

ABSTRACT

The most common site of breast cancer metastasis is the bone, occurring in approximately 70% of patients with advanced disease. Bone metastasis is associated with severe morbidities and high mortality. Therefore, deeper understanding of the mechanisms that enable bone-metastatic relapse are urgently needed. We report the establishment and characterization of a bone-seeking variant of breast cancer cells that spontaneously forms aggressive bone metastases following surgical resection of primary tumor. We characterized the modifications in the immune milieu during early and late stages of metastatic relapse and found that the formation of bone metastases is associated with systemic changes, as well as modifications of the bone microenvironment towards an immune suppressive milieu. Furthermore, we characterized the intrinsic changes in breast cancer cells that facilitate bone-tropism and found that they acquire mesenchymal and osteomimetic features. This model provides a clinically relevant platform to study the functional interactions between breast cancer cells and the bone microenvironment, in an effort to identify novel targets for intervention.


Subject(s)
Bone Neoplasms/immunology , Bone Neoplasms/secondary , Breast Neoplasms/immunology , Immune Tolerance , Animals , Disease Models, Animal , Epithelial-Mesenchymal Transition/immunology , Female , Mice, Inbred BALB C , Neoplasm Transplantation , Tumor Microenvironment/immunology
6.
Int J Cancer ; 145(9): 2521-2534, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31216364

ABSTRACT

The major cause of melanoma mortality is metastasis to distant organs, including lungs and brain. Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable "premetastatic niche." Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma-derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound-healing functions, suggesting that tumor cell-secreted EVs activate distinct CAF characteristics and tumor-promoting functions. Moreover, melanoma-secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV-mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma-derived EVs reprogram tumor-promoting functions in stromal cells in a distinct manner, implicating a central role for tumor-derived EV signaling in promoting the formation of an inflammatory metastatic niche.


Subject(s)
Extracellular Vesicles/pathology , Inflammation/pathology , Melanoma/pathology , Signal Transduction/physiology , Tumor Microenvironment/physiology , Animals , Astrocytes/pathology , Exosomes/pathology , Fibroblasts/pathology , Male , Mice , Mice, Inbred C57BL , NIH 3T3 Cells , Paracrine Communication/physiology , Stromal Cells/pathology
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