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1.
Nat Immunol ; 25(7): 1257-1269, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38806707

ABSTRACT

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.


Subject(s)
B7-H1 Antigen , Circadian Clocks , Immune Checkpoint Inhibitors , Myeloid-Derived Suppressor Cells , Animals , Mice , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Circadian Clocks/immunology , B7-H1 Antigen/metabolism , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Mice, Inbred C57BL , Circadian Rhythm/immunology , CD8-Positive T-Lymphocytes/immunology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/therapy , Colorectal Neoplasms/drug therapy , Tumor Microenvironment/immunology , Immune Tolerance , Humans , Female , Cell Line, Tumor , Single-Cell Analysis , Immunosuppression Therapy , Cytokines/metabolism , Male
2.
Nat Cell Biol ; 25(12): 1848-1859, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37957324

ABSTRACT

Breast cancer brain metastasis (BCBM) is a lethal disease with no effective treatments. Prior work has shown that brain cancers and metastases are densely infiltrated with anti-inflammatory, protumourigenic tumour-associated macrophages, but the role of brain-resident microglia remains controversial because they are challenging to discriminate from other tumour-associated macrophages. Using single-cell RNA sequencing, genetic and humanized mouse models, we specifically identify microglia and find that they play a distinct pro-inflammatory and tumour-suppressive role in BCBM. Animals lacking microglia show increased metastasis, decreased survival and reduced natural killer and T cell responses, showing that microglia are critical to promote anti-tumour immunity to suppress BCBM. We find that the pro-inflammatory response is conserved in human microglia, and markers of their response are associated with better prognosis in patients with BCBM. These findings establish an important role for microglia in anti-tumour immunity and highlight them as a potential immunotherapy target for brain metastasis.


Subject(s)
Brain Neoplasms , Breast Neoplasms , Mice , Animals , Humans , Female , Microglia , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Brain Neoplasms/pathology , Brain/pathology , Treatment Outcome
3.
Nat Genet ; 55(4): 595-606, 2023 04.
Article in English | MEDLINE | ID: mdl-36914836

ABSTRACT

Women with germline BRCA1 mutations (BRCA1+/mut) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1+/mut is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1+/mut and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1+/mut stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1+/mut may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation.


Subject(s)
Breast Neoplasms , Mammary Glands, Human , Female , Humans , Mutation , BRCA1 Protein/genetics , Breast Neoplasms/pathology , Cell Transformation, Neoplastic/metabolism , Mammary Glands, Human/metabolism , Carcinogenesis/pathology , Stromal Cells/pathology
4.
Clin Exp Metastasis ; 39(2): 263-277, 2022 04.
Article in English | MEDLINE | ID: mdl-35072851

ABSTRACT

While immense strides have been made in understanding tumor biology and in developing effective treatments that have substantially improved the prognosis of cancer patients, metastasis remains the major cause of cancer-related death. Improvements in the detection and treatment of primary tumors are contributing to a growing, detailed understanding of the dynamics of metastatic progression. Yet challenges remain in detecting metastatic dissemination prior to the establishment of overt metastases and in predicting which patients are at the highest risk of developing metastatic disease. Further improvements in understanding the mechanisms governing metastasis have great potential to inform the adaptation of existing therapies and the development of novel approaches to more effectively control metastatic disease. This article presents a forward-looking perspective on the challenges that remain in the treatment of metastasis, and the exciting emerging approaches that promise to transform the treatment of metastasis in cancer patients.


Subject(s)
Neoplasms , Humans , Neoplasm Metastasis , Neoplasms/pathology , Neoplasms/therapy , Prognosis
5.
Nat Cancer ; 3(4): 486-504, 2022 04.
Article in English | MEDLINE | ID: mdl-35469015

ABSTRACT

Disseminated cancer cells frequently lodge near vasculature in secondary organs. However, our understanding of the cellular crosstalk invoked at perivascular sites is still rudimentary. Here, we identify intercellular machinery governing formation of a pro-metastatic vascular niche during breast cancer colonization in the lung. We show that specific secreted factors, induced in metastasis-associated endothelial cells (ECs), promote metastasis in mice by enhancing stem cell properties and the viability of cancer cells. Perivascular macrophages, activated via tenascin C (TNC) stimulation of Toll-like receptor 4 (TLR4), were shown to be crucial in niche activation by secreting nitric oxide (NO) and tumor necrosis factor (TNF) to induce EC-mediated production of niche components. Notably, this mechanism was independent of vascular endothelial growth factor (VEGF), a key regulator of EC behavior and angiogenesis. However, targeting both macrophage-mediated vascular niche activation and VEGF-regulated angiogenesis resulted in added potency to curb lung metastasis in mice. Together, our findings provide mechanistic insights into the formation of vascular niches in metastasis.


Subject(s)
Lung Neoplasms , Macrophages , Tenascin , Animals , Endothelial Cells/metabolism , Lung/blood supply , Lung/metabolism , Lung Neoplasms/blood supply , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Macrophages/metabolism , Macrophages/pathology , Mice , Neovascularization, Pathologic/pathology , Tenascin/metabolism , Vascular Endothelial Growth Factor A/metabolism
6.
Cancer Discov ; 11(3): 638-659, 2021 03.
Article in English | MEDLINE | ID: mdl-33060108

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which challenges the molecular analyses of bulk tumor samples. Here we FACS-purified epithelial cells from human PDAC and normal pancreas and derived their genome-wide transcriptome and DNA methylome landscapes. Clustering based on DNA methylation revealed two distinct PDAC groups displaying different methylation patterns at regions encoding repeat elements. Methylationlow tumors are characterized by higher expression of endogenous retroviral transcripts and double-stranded RNA sensors, which lead to a cell-intrinsic activation of an interferon signature (IFNsign). This results in a protumorigenic microenvironment and poor patient outcome. Methylationlow/IFNsignhigh and Methylationhigh/IFNsignlow PDAC cells preserve lineage traits, respective of normal ductal or acinar pancreatic cells. Moreover, ductal-derived Kras G12D/Trp53 -/- mouse PDACs show higher expression of IFNsign compared with acinar-derived counterparts. Collectively, our data point to two different origins and etiologies of human PDACs, with the aggressive Methylationlow/IFNsignhigh subtype potentially targetable by agents blocking intrinsic IFN signaling. SIGNIFICANCE: The mutational landscapes of PDAC alone cannot explain the observed interpatient heterogeneity. We identified two PDAC subtypes characterized by differential DNA methylation, preserving traits from normal ductal/acinar cells associated with IFN signaling. Our work suggests that epigenetic traits and the cell of origin contribute to PDAC heterogeneity.This article is highlighted in the In This Issue feature, p. 521.


Subject(s)
Carcinoma, Pancreatic Ductal/etiology , Carcinoma, Pancreatic Ductal/metabolism , DNA Methylation , Interferons/metabolism , Pancreatic Neoplasms/etiology , Pancreatic Neoplasms/metabolism , Repetitive Sequences, Nucleic Acid , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/pathology , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , CpG Islands , Disease Progression , Disease Susceptibility , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Models, Biological , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Prognosis , Reproducibility of Results , Signal Transduction , Transcriptome , Tumor Microenvironment/genetics
7.
Nat Commun ; 11(1): 1494, 2020 03 20.
Article in English | MEDLINE | ID: mdl-32198421

ABSTRACT

Metastatic colonization relies on interactions between disseminated cancer cells and the microenvironment in secondary organs. Here, we show that disseminated breast cancer cells evoke phenotypic changes in lung fibroblasts, forming a supportive metastatic niche. Colonization of the lungs confers an inflammatory phenotype in metastasis-associated fibroblasts. Specifically, IL-1α and IL-1ß secreted by breast cancer cells induce CXCL9 and CXCL10 production in lung fibroblasts via NF-κB signaling, fueling the growth of lung metastases. Notably, we find that the chemokine receptor CXCR3, that binds CXCL9/10, is specifically expressed in a small subset of breast cancer cells, which exhibits tumor-initiating ability when co-transplanted with fibroblasts and has high JNK signaling that drives IL-1α/ß expression. Importantly, disruption of the intercellular JNK-IL-1-CXCL9/10-CXCR3 axis reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for the molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis.


Subject(s)
Breast Neoplasms/metabolism , Fibroblasts/metabolism , Lung Neoplasms/metabolism , Lung/metabolism , Neoplasm Metastasis , Tumor Microenvironment/physiology , Animals , Breast/metabolism , Breast/pathology , Breast Neoplasms/pathology , Cell Line, Tumor , Chemokine CXCL10/metabolism , Chemokine CXCL9/metabolism , Female , Fibroblasts/pathology , Gene Knockdown Techniques , Humans , Interleukin-1alpha/metabolism , Interleukin-1beta/metabolism , Lung/pathology , Lung Neoplasms/pathology , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Receptors, CXCR3/metabolism , Signal Transduction , Transcriptome , Transplantation, Heterologous
8.
EMBO Mol Med ; 10(10)2018 10.
Article in English | MEDLINE | ID: mdl-30190333

ABSTRACT

Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c-Jun N-terminal kinase (JNK) pathway, leading to reduced therapeutic efficacy. We find that elevated JNK activity in cancer cells is linked to poor clinical outcome in breast cancer patients and is critical for tumor initiation and metastasis in xenograft mouse models of breast cancer. We show that JNK signaling enhances expression of the ECM and stem cell niche components osteopontin, also called secreted phosphoprotein 1 (SPP1), and tenascin C (TNC), that promote lung metastasis. We demonstrate that both SPP1 and TNC are direct targets of the c-Jun transcription factor. Exposure to multiple chemotherapies further exploits this JNK-mediated axis to confer treatment resistance. Importantly, JNK inhibition or disruption of SPP1 or TNC expression sensitizes experimental mammary tumors and metastases to chemotherapy, thus providing insights to consider for future treatment strategies against metastatic breast cancer.


Subject(s)
Breast Neoplasms/physiopathology , Drug Resistance, Neoplasm , Neoplasm Metastasis/physiopathology , Signal Transduction , Animals , Cell Movement , Cell Proliferation , Disease Models, Animal , Extracellular Matrix/metabolism , Female , Heterografts , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Mice , Neoplasm Transplantation , Neoplastic Stem Cells/physiology
9.
Adv Drug Deliv Rev ; 97: 41-55, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26743193

ABSTRACT

The extracellular matrix (ECM) is increasingly recognized as an important regulator in breast cancer. ECM in breast cancer development features numerous changes in composition and organization when compared to the mammary gland under homeostasis. Matrix proteins that are induced in breast cancer include fibrillar collagens, fibronectin, specific laminins and proteoglycans as well as matricellular proteins. Growing evidence suggests that many of these induced ECM proteins play a major functional role in breast cancer progression and metastasis. A number of the induced ECM proteins have moreover been shown to be essential components of metastatic niches, promoting stem/progenitor signaling pathways and metastatic growth. ECM remodeling enzymes are also markedly increased, leading to major changes in the matrix structure and biomechanical properties. Importantly, several ECM components and ECM remodeling enzymes are specifically induced in breast cancer or during tissue regeneration while healthy tissues under homeostasis express exceedingly low levels. This may indicate that ECM and ECM-associated functions may represent promising drug targets against breast cancer, providing important specificity that could be utilized when developing therapies.


Subject(s)
Breast Neoplasms/metabolism , Extracellular Matrix/metabolism , Animals , Breast Neoplasms/therapy , Female , Humans
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