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1.
Cancer Discov ; 14(7): 1302-1323, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38683161

ABSTRACT

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development. Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression. See related article by Belle et al., p. 1324.


Subject(s)
Breast Neoplasms , Cancer-Associated Fibroblasts , Disease Progression , Tumor Microenvironment , Animals , Female , Mice , Humans , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/immunology , Tumor Microenvironment/immunology , Killer Cells, Natural/immunology , Cellular Senescence/immunology
2.
Cancer Discov ; 13(6): 1454-1477, 2023 06 02.
Article in English | MEDLINE | ID: mdl-36883955

ABSTRACT

Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKα inhibition (p38i) limits tumor growth by reprogramming the metastatic tumor microenvironment in a CD4+ T cell-, IFNγ-, and macrophage-dependent manner. To identify targets that further increased p38i efficacy, we utilized a stromal labeling approach and single-cell RNA sequencing. Thus, we combined p38i and an OX40 agonist that synergistically reduced metastatic growth and increased overall survival. Intriguingly, patients with a p38i metastatic stromal signature had better overall survival that was further improved by the presence of an increased mutational load, leading us to ask if our approach would be effective in antigenic breast cancer. The combination of p38i, anti-OX40, and cytotoxic T-cell engagement cured mice of metastatic disease and produced long-term immunologic memory. Our findings demonstrate that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies. SIGNIFICANCE: Immunotherapy is rarely effective in breast cancer. We dissected the metastatic tumor stroma, which revealed a novel therapeutic approach that targets the stromal p38MAPK pathway and creates an opportunity to unleash an immunologic response. Our work underscores the importance of understanding the tumor stromal compartment in therapeutic design. This article is highlighted in the In This Issue feature, p. 1275.


Subject(s)
Neoplasms , Mice , Animals , T-Lymphocytes, Cytotoxic , CD4-Positive T-Lymphocytes , Immunotherapy , Macrophages , Tumor Microenvironment , Cell Line, Tumor
3.
Nat Cell Biol ; 24(6): 812-814, 2022 06.
Article in English | MEDLINE | ID: mdl-35654838
4.
Oncotarget ; 11(40): 3621-3632, 2020 Oct 06.
Article in English | MEDLINE | ID: mdl-33088423

ABSTRACT

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive versus suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field.

5.
Cancer Res ; 80(5): 1171-1182, 2020 03 01.
Article in English | MEDLINE | ID: mdl-31932453

ABSTRACT

Chemotherapy is important for cancer treatment, however, toxicities limit its use. While great strides have been made to ameliorate the acute toxicities induced by chemotherapy, long-term comorbidities including bone loss remain a significant problem. Chemotherapy-driven estrogen loss is postulated to drive bone loss, but significant data suggests the existence of an estrogen-independent mechanism of bone loss. Using clinically relevant mouse models, we showed that senescence and its senescence-associated secretory phenotype (SASP) contribute to chemotherapy-induced bone loss that can be rescued by depleting senescent cells. Chemotherapy-induced SASP could be limited by targeting the p38MAPK-MK2 pathway, which resulted in preservation of bone integrity in chemotherapy-treated mice. These results transform our understanding of chemotherapy-induced bone loss by identifying senescent cells as major drivers of bone loss and the p38MAPK-MK2 axis as a putative therapeutic target that can preserve bone and improve a cancer survivor's quality of life. SIGNIFICANCE: Senescence drives chemotherapy-induced bone loss that is rescued by p38MAPK or MK2 inhibitors. These findings may lead to treatments for therapy-induced bone loss, significantly increasing quality of life for cancer survivors.


Subject(s)
Antineoplastic Agents/adverse effects , Cellular Senescence/drug effects , MAP Kinase Signaling System/drug effects , Neoplasms/drug therapy , Osteoporosis/chemically induced , Animals , Disease Models, Animal , Doxorubicin/adverse effects , Femur/cytology , Femur/diagnostic imaging , Femur/pathology , Humans , Injections, Intraperitoneal , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Transgenic , Osteoporosis/diagnosis , Osteoporosis/pathology , Paclitaxel/adverse effects , Protein Serine-Threonine Kinases/metabolism , X-Ray Microtomography , p38 Mitogen-Activated Protein Kinases/metabolism
6.
Nat Rev Cancer ; 19(8): 439-453, 2019 08.
Article in English | MEDLINE | ID: mdl-31235879

ABSTRACT

Cellular senescence plays a critical role in tumorigenesis. Once thought of as a tissue culture artefact by some researchers, senescence is now a major field of study. Although there are common molecular mechanisms that enforce the growth arrest that characterizes the phenotype, the impact of senescence is varied and can, in some instances, have opposite effects on tumorigenesis. It has become clearer that the cell of origin and the tissue in question dictate the impact of senescence on tumorigenesis. In this Review, we unravel this complexity by focusing on how senescence impacts tumorigenesis when it arises within incipient tumour cells versus stromal cells, and how these roles can change in different stages of disease progression. In addition, we highlight the diversity of the senescent phenotype and its functional output beyond growth arrest: the senescence-associated secretory phenotype (SASP). Fortunately, a number of new genetic and pharmacologic tools have been developed that are now allowing the senescence phenotype to be parsed further.


Subject(s)
Cell Transformation, Neoplastic , Cellular Senescence/genetics , Neoplasms/pathology , Antineoplastic Agents/pharmacology , Apoptosis , DNA Damage , Disease Progression , Fibroblasts/metabolism , Humans , Immune System , Neoplasms/genetics , Phenotype , Promoter Regions, Genetic
7.
Cancer Res ; 78(19): 5618-5630, 2018 10 01.
Article in English | MEDLINE | ID: mdl-30093561

ABSTRACT

The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPKα could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase MK2 each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. This effect was primarily mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity that drastically affects quality of life for patients with cancer. These data underscore the vital role played by stromal-derived factors in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss.Significance: Pharmacologically targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth, preserves bone quality, and extends survival. Cancer Res; 78(19); 5618-30. ©2018 AACR.


Subject(s)
Antineoplastic Agents/adverse effects , Bone and Bones/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Administration, Oral , Animals , Bone Neoplasms/secondary , Bone and Bones/pathology , Breast Neoplasms/pathology , Cell Line, Tumor , Disease Progression , Drug Therapy , Female , HEK293 Cells , Humans , Induction Chemotherapy , MAP Kinase Signaling System , Macrophages/metabolism , Mice , Neoplasm Metastasis , Osteoclasts/metabolism , Paclitaxel/pharmacology , Prognosis , Quality of Life , Stromal Cells/metabolism , Tumor Microenvironment
8.
Cell Cycle ; 15(17): 2346-59, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27399331

ABSTRACT

The NFAT family of transcription factors has been primarily related to T cell development, activation, and differentiation. Further studies have shown that these ubiquitous proteins are observed in many cell types inside and outside the immune system, and are involved in several biological processes, including tumor growth, angiogenesis, and invasiveness. However, the specific role of the NFAT1 family member in naive B cell proliferation remains elusive. Here, we demonstrate that NFAT1 transcription factor controls Cyclin E expression, cell proliferation, and tumor growth in vivo. Specifically, we show that inducible expression of NFAT1 inhibits cell cycle progression, reduces colony formation, and controls tumor growth in nude mice. We also demonstrate that NFAT1-deficient naive B lymphocytes show a hyperproliferative phenotype and high levels of Cyclin E1 and E2 upon BCR stimulation when compared to wild-type B lymphocytes. NFAT1 transcription factor directly regulates Cyclin E expression in B cells, inhibiting the G1/S cell cycle phase transition. Bioinformatics analysis indicates that low levels of NFAT1 correlate with high expression of Cyclin E1 in different human cancers, including Diffuse Large B-cell Lymphomas (DLBCL). Together, our results demonstrate a repressor role for NFAT1 in cell cycle progression and Cyclin E expression in B lymphocytes, and suggest a potential function for NFAT1 protein in B cell malignancies.


Subject(s)
B-Lymphocytes/metabolism , Cell Cycle , NFATC Transcription Factors/metabolism , Animals , CHO Cells , Cell Cycle Checkpoints , Cell Proliferation , Cricetinae , Cricetulus , Cyclin E , Humans , Jurkat Cells , Lymphoma, B-Cell/pathology , Mice, Inbred BALB C , Mice, Nude , Promoter Regions, Genetic/genetics
9.
J Leukoc Biol ; 100(5): 1081-1091, 2016 11.
Article in English | MEDLINE | ID: mdl-27286791

ABSTRACT

CD4 T cell activation and differentiation mechanisms constitute a complex and intricate signaling network involving several regulatory proteins. IRF2BP2 is a transcriptional repressor that is involved in gene-expression regulation in very diverse biologic contexts. Information regarding the IRF2BP2 regulatory function in CD4 T lymphocytes is very limited and suggests a role for this protein in repressing the expression of different cytokine genes. Here, we showed that Irf2bp2 gene expression was decreased in CD4 T cells upon activation. To investigate the possible regulatory roles for IRF2BP2 in CD4 T cell functions, this protein was ectopically expressed in murine primary-activated CD4 T lymphocytes through retroviral transduction. Interestingly, ectopic expression of IRF2BP2 led to a reduction in CD25 expression and STAT5 phosphorylation, along with an impaired proliferative capacity. The CD69 expression was also diminished in IRF2BP2-overexpressing cells, whereas CD44 and CD62L levels were not altered. In vivo, transferred, IRF2BP2-overexpressing, transduced cells displayed an impaired expansion capacity compared with controls. Furthermore, overexpression of IRF2BP2 in differentiated Th cells resulted in slightly reduced IL-4 and pro-TGF-ß production in Th2 and iTregs but had no effect on IFN-γ or IL-17 expression in Th1 and Th17 cells, respectively. Taken together, our data suggest a role for IRF2BP2 in regulating CD4 T cell activation by repressing proliferation and the expression of CD25 and CD69 induced by TCR stimuli.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Lymphocyte Activation/immunology , Receptors, Antigen, T-Cell/immunology , Transcription Factors/immunology , Animals , Antigens, CD/biosynthesis , Antigens, CD/genetics , Antigens, Differentiation, T-Lymphocyte/biosynthesis , Antigens, Differentiation, T-Lymphocyte/genetics , Apoptosis/immunology , Cells, Cultured , Cytokines/biosynthesis , Cytokines/genetics , Female , Gene Expression Regulation/immunology , Humans , Interleukin-2 Receptor alpha Subunit/biosynthesis , Interleukin-2 Receptor alpha Subunit/genetics , Lectins, C-Type/biosynthesis , Lectins, C-Type/genetics , Lymphocyte Activation/genetics , Male , Mice , Mice, Inbred C57BL , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Radiation Chimera , Recombinant Fusion Proteins/metabolism , STAT5 Transcription Factor/metabolism , Transduction, Genetic
10.
Mol Cell Biol ; 36(1): 119-31, 2016 Jan 01.
Article in English | MEDLINE | ID: mdl-26483414

ABSTRACT

The NFAT (nuclear factor of activated T cells) family of transcription factors is composed of four calcium-responsive proteins (NFAT1 to -4). The NFAT2 (also called NFATc1) gene encodes the isoforms NFAT2α and NFAT2ß that result mainly from alternative initiation exons that provide two different N-terminal transactivation domains. However, the specific roles of the NFAT2 isoforms in cell physiology remain unclear. Because previous studies have shown oncogenic potential for NFAT2, this study emphasized the role of the NFAT2 isoforms in cell transformation. Here, we show that a constitutively active form of NFAT2α (CA-NFAT2α) and CA-NFAT2ß distinctly control death and transformation in NIH 3T3 cells. While CA-NFAT2α strongly induces cell transformation, CA-NFAT2ß leads to reduced cell proliferation and intense cell death through the upregulation of tumor necrosis factor alpha (TNF-α). CA-NFAT2ß also increases cell death and upregulates Fas ligand (FasL) and TNF-α in CD4(+) T cells. Furthermore, we demonstrate that differential roles of NFAT2 isoforms in NIH 3T3 cells depend on the N-terminal domain, where the NFAT2ß-specific N-terminal acidic motif is necessary to induce cell death. Interestingly, the NFAT2α isoform is upregulated in Burkitt lymphomas, suggesting an isoform-specific involvement of NFAT2 in cancer development. Finally, our data suggest that alternative N-terminal domains of NFAT2 could provide differential mechanisms for the control of cellular functions.


Subject(s)
Cell Transformation, Neoplastic/genetics , NFATC Transcription Factors/genetics , Animals , Apoptosis/physiology , Cell Death , Cell Proliferation/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation , Humans , NFATC Transcription Factors/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism
11.
PLoS One ; 7(10): e47868, 2012.
Article in English | MEDLINE | ID: mdl-23110116

ABSTRACT

The proteins belonging to the nuclear factor of activated T cells (NFAT) family of transcription factors are expressed in several cell types and regulate genes involved in differentiation, cell cycle and apoptosis. NFAT proteins share two conserved domains, the NFAT-homology region (NHR) and a DNA-binding domain (DBD). The N- and C-termini display two transactivation domains (TAD-N and TAD-C) that have low sequence similarity. Due to the high sequence conservation in the NHR and DBD, NFAT members have some overlapping roles in gene regulation. However, several studies have shown distinct roles for NFAT proteins in the regulation of cell death. The TAD-C shows low sequence similarity among NFAT family members, but its contribution to specific NFAT1-induced phenotypes is poorly understood. Here, we described at least two regions of NFAT1 TAD-C that confer pro-apoptotic activity to NFAT1. These regions extend from amino acids 699 to 734 and 819 to 850 of NFAT1. We also showed that the NFAT1 TAD-C is unable to induce apoptosis by itself and requires a functional DBD. Furthermore, we showed that when fused to NFAT1 TAD-C, NFAT2, which is associated with cell transformation, induces apoptosis in fibroblasts. Together, these results suggest that the NFAT1 TAD-C includes NFAT death domains that confer to different NFAT members the ability to induce apoptosis.


Subject(s)
Apoptosis/genetics , Gene Expression Regulation/genetics , Multigene Family/genetics , NFATC Transcription Factors/genetics , Trans-Activators/genetics , Animals , Blotting, Western , DNA Primers/genetics , Electrophoretic Mobility Shift Assay , Gentian Violet , Mice , NIH 3T3 Cells , Plasmids/genetics , Protein Structure, Tertiary
12.
Oncol Lett ; 2(1): 109-114, 2011 Jan.
Article in English | MEDLINE | ID: mdl-22870138

ABSTRACT

Anti-tumor antibodies act as biomarkers for the early diagnosis of prostate cancer (PCa). Osteopontin (OPN) is overexpressed in PCa cells and contributes to the progression of the disease. This study aimed to evaluate whether OPN evokes a humoral immune response in PCa patients and whether the reactivity levels of anti-OPN antibodies may be used to better differentiate PCa from benign and healthy donor plasma samples. Plasma samples from biopsy-proven PCa patients (29), benign prostate hyperplasia (BPH) (18) and control healthy donors (HD) (30) were tested by immunoblots using the recombinant human OPN. The frequency of anti-OPN antibodies was significantly higher in PCa (66%) plasma samples as compared to BPH (33%) and HD controls (10%). Anti-OPN antibodies were detected in a high proportion of plasma samples from patients with a Gleason score of less than 6 (57%), prostate-specific antigen levels lower than 10 ng/ml (67%) and pT2 organ-confined disease (70%), suggesting that anti-OPN antibodies may be used as an early serum marker for PCa. To the best of our knowledge, this is the first description of OPN as a tumor autoantigen and one of the most reactive individual autoantigens described thus far. These data support the inclusion of OPN in a multiplex of tumor antigens in order to perform antibody profiling in PCa as well as in other malignancies overexpressing OPN.

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