scholarly journals Aicardi-Goutières Syndrome gene Rnaseh2c is a metastasis susceptibility gene in breast cancer

2019 ◽  
Author(s):  
Sarah K. Deasy ◽  
Ryo Uehara ◽  
Suman K. Vodnala ◽  
Howard H. Yang ◽  
Randall A. Dass ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
The United States ◽  
Breast Cancer Metastasis ◽  
Rnase H2

AbstractBreast cancer is the second leading cause of cancer-related deaths in the United States, with the majority of these deaths due to metastatic lesions rather than the primary tumor. Thus, a better understanding of the etiology of metastatic disease is crucial for improving survival. Using a haplotype mapping strategy in mouse and shRNA-mediated gene knockdown, we identified Rnaseh2c, a scaffolding protein of the heterotrimeric RNase H2 endoribonuclease complex, as a novel metastasis susceptibility factor. We found that the role of Rnaseh2c in metastatic disease is independent of RNase H2 enzymatic activity, and immunophenotyping and RNA-sequencing analysis revealed engagement of the T cell-mediated adaptive immune response. Furthermore, the cGAS-Sting pathway was not activated in the metastatic cancer cells used in this study, suggesting that the mechanism of immune response in breast cancer is different from the mechanism proposed for Aicardi-Goutières Syndrome, a rare interferonopathy caused by RNase H2 mutation. These results suggest an important novel, non-enzymatic role for RNASEH2C during breast cancer progression and add Rnaseh2c to a panel of genes we have identified that together could determine patients with high risk for metastasis. These results also highlight a potential new target for combination with immunotherapies and may contribute to a better understanding of the etiology of Aicardi-Goutières Syndrome autoimmunity.Author SummaryThe majority of breast cancer-associated deaths are due to metastatic disease, the process where cancerous cells leave the primary tumor in the breast and spread to a new location in the body. To better understand the etiology of this process, we investigate the effects of gene expression changes in the primary tumor. In this study, we found that changing the expression of the gene Rnaseh2c changed the number of metastases that developed in the lungs of tumor-bearing mice. By investigating the enzyme complex Rnaseh2c is part of, RNase H2, we determined that Rnaseh2c’s effects may be independent of RNase H2 enzyme activity. Because Rnaseh2c is known to cause the autoimmune disease Aicardi-Goutières Syndrome (AGS), we tested whether the immune system is involved in the metastatic effect. Indeed, we found that the cytotoxic T cell response is important for mediating the effect that Rnaseh2c has on metastasis. Together these data indicate that Rnaseh2c expression contributes to a patient’s susceptibility to developing breast cancer metastasis and demonstrate that the immune system is involved in this outcome. The implications of this study suggest immunotherapy could be a viable treatment for breast cancer metastasis and may help inform the understanding of AGS and RNase H2 in cancer.

Next Generation of Immunotherapy for Melanoma

2008 ◽  
Vol 26 (20) ◽  
pp. 3445-3455 ◽  
Author(s):  
John M. Kirkwood ◽  
Ahmad A. Tarhini ◽  
Monica C. Panelli ◽  
Stergios J. Moschos ◽  
Hassane M. Zarour ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
The United States ◽  
Cytotoxic Agents ◽  
Antitumor Immune Response ◽  
Phase Iii

PurposeImmunotherapy has a long history with striking but limited success in patients with melanoma. To date, interleukin-2 and interferon-alfa2b are the only approved immunotherapeutic agents for melanoma in the United States.DesignTumor evasion of host immune responses, and strategies for overcoming tumor-induced immunosuppression are reviewed. Several novel immunotherapies currently in worldwide phase III clinical testing for melanoma are discussed.ResultsThe limitations of immunotherapy for melanoma stem from tumor-induced mechanisms of immune evasion that render the host tolerant of tumor antigens. For example, melanoma inhibits the maturation of antigen-presenting cells, preventing full T-cell activation and downregulating the effector antitumor immune response. New immunotherapies targeting critical regulatory elements of the immune system may overcome tolerance and promote a more effective antitumor immune response. These include monoclonal antibodies that block the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and toll-like receptor 9 (TLR9) agonists. Blockade of CTLA4 prevents inhibitory signals that downregulate T-cell activation. TLR9 agonists stimulate dendritic cell maturation and ultimately induce a more effective immune response. These approaches have been shown to stimulate acute immune activation with concomitant appearance of transient adverse events mediated by the immune system. The pattern and duration of immune responses associated with these new modalities differ from those associated with cytokines and cytotoxic agents. In addition, vaccines are being developed that may ultimately target melanoma either alone or in combination with these immunomodulatory therapies.ConclusionThe successes of cytokine and interferon therapy of melanoma, coupled with an array of new approaches, are generating new enthusiasm for the immunotherapy of melanoma.

scholarly journals The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the “Seed” and the “Soil”?

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Jenny E. Chu ◽  
Alison L. Allan
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Metastatic Disease ◽  
Cancer Metastasis ◽  
Metastatic Breast ◽  
Therapy Resistance ◽  
Breast Cancer Metastasis ◽  
Specific Pattern ◽  
Organ Tropism

Breast cancer is a prevalent disease worldwide, and the majority of deaths occur due to metastatic disease. Clinical studies have identified a specific pattern for the metastatic spread of breast cancer, termed organ tropism; where preferential secondary sites include lymph node, bone, brain, lung, and liver. A rare subpopulation of tumor cells, the cancer stem cells (CSCs), has been hypothesized to be responsible for metastatic disease and therapy resistance. Current treatments are highly ineffective against metastatic breast cancer, likely due to the innate therapy resistance of CSCs and the complex interactions that occur between cancer cells and their metastatic microenvironments. A better understanding of these interactions is essential for the development of novel therapeutic targets for metastatic disease. This paper summarizes the characteristics of breast CSCs and their potential metastatic microenvironments. Furthermore, it raises the question of the existence of a CSC niche and highlights areas for future investigation.

scholarly journals Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

2015 ◽  
Vol 4 (3) ◽  
pp. e995562 ◽  
Author(s):  
Simon Gebremeskel ◽  
Daniel R. Clattenburg ◽  
Drew Slauenwhite ◽  
Lynnea Lobert ◽  
Brent Johnston
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Natural Killer T Cell ◽  
Killer T Cell ◽  
Natural Killer T

scholarly journals Phosphorylation of serine 367 of FOXC2 by p38 regulates ZEB1 and breast cancer metastasis, without impacting primary tumor growth

Oncogene ◽  
2016 ◽  
Vol 35 (46) ◽  
pp. 5977-5988 ◽  
Author(s):  
S J Werden ◽  
N Sphyris ◽  
T R Sarkar ◽  
A N Paranjape ◽  
A M LaBaff ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Primary Tumor Growth

scholarly journals Metastasis-specific gene expression in autochthonous and allograft mouse mammary tumor models: stratification and identification of targetable signatures

2019 ◽  
Author(s):  
Christina Ross ◽  
Karol Szczepanek ◽  
Maxwell lee ◽  
Howard Yang ◽  
Cody J. Peer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Line ◽  
Mouse Models ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Specific Gene ◽  
Tail Vein ◽  
Specific Gene Expression

AbstractBreast cancer is a leading cause of cancer-related death of women in the U.S., which is ultimately due to metastasis rather than primary tumor burden. Therefore, increased understanding of metastasis to develop novel therapies is critical in reducing breast cancer-related mortality. Indeed, a major hurdle in advancing metastasis-targeted intervention is the genotypic and phenotypic heterogeneity that exists between primary and secondary lesions. To identify targetable metastasis-specific gene expression profiles we performed RNA sequencing of breast cancer metastasis mouse models. We analyzed metastases from models of various oncogenic drivers and routes, including orthotopic injection, tail vein injection, intracardiac injection, and genetically engineered mouse models (GEMMs). Herein, we analyzed samples from 176 mice and tissue culture samples, resulting in 338 samples total. Using these data, we contrasted the different breast cancer metastasis models, and also identified common, targetable metastasis specific gene expression signatures.Principal component analysis revealed that mouse model (Allograft v. GEMM) rather than tissue source (PT v metastatic nodule) shaped the transcriptomes of our samples. Allograft models exhibited more mesenchymal-like gene expression than GEMM models, and primary culturing of GEMM-derived metastatic tissue induced more mesenchymal-like gene expression. Furthermore, metastasis-specific gene expression differed between tail vein and orthotopic injection models of the same cell line, the degree of which was cell line dependent. Finally, we examined metastasis-specific gene expression common to models of spontaneous metastasis (orthotopic injection and GEMMs). Pathway analysis identified upregulation of the sildenafil response, and nicotine degradation pathways. The influence of these pathways on metastatic spread was assessed by treatment of allograft models with clinically relevant dosing of sildenafil or nicotine. Sildenafil significantly reduced pulmonary metastasis while nicotine administration significantly increased metastasis, and neither regimen altered primary tumor mass. Taken together our data reveals critical differences between pre-clinical models of metastatic breast cancer. Additionally, this strategy has identified clinically targetable metastasis-specific pathways integral to metastatic spread.

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