Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer

Lan, Qiang; Peyvandi, Sanam; Duffey, Nathalie; Huang, Yu-Ting; Barras, David; Held, Werner; Richard, François; Delorenzi, Mauro; Sotiriou, Christos; Desmedt, Christine; Lorusso, Girieca; Rüegg, Curzio

doi:10.1038/s41388-018-0624-2

Cited by 96 publications

(129 citation statements)

References 51 publications

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“…Meanwhile, an association of human Tregs, neutrophils and inflammatory mediators such as interferon-gamma (IFNγ) are rather context-dependent [109]. With regards to the role of other interferons, a recent study demonstrated the role of IFN-β-induced immunological dormancy reflected in sustained activation of the IRF7/IFN-β/IFNAR axis in chemo-resistant (high dose doxorubicin and methotrexate) ER-negative 4T1 breast cancer cells in vitro and in vivo [110]. Meanwhile, one study to recapitulate sustained inflammation in lungs as demonstrated in smoker individuals revealed that neutrophil extracellular traps (NETs) proteases (elastase and MMP9) produced during inflammation can degrade laminin which further induces proliferation of dormant cells through activating αvβ3 integrin signaling, resulting in aggressive metastatic tumors in mice [111].…”

Section: Cancer Immune-mediated Dormancymentioning

confidence: 99%

Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer

Jahanban‐Esfahlan

Seidi

Manjili

et al. 2019

Cancers

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Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including angiogenic switch, immune escape, cancer stem cells, extracellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer and discuss the implications of such approaches in cancer treatment.

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Section: Cancer Immune-mediated Dormancymentioning

confidence: 99%

Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer

Jahanban‐Esfahlan

Seidi

Manjili

et al. 2019

Cancers

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“…It was recently demonstrated that chemotherapies elicit a state of immunological dormancy in ER-negative breast cancers, marked by sustained type-I IFN signaling, reduced cell growth, and longer progression-free survival(Lan et al, 2019). This indicates a possible shared mechanism between chemotherapy-induced immunological dormancy and ADAR1-dependency in TNBC.…”

Section: Discussionmentioning

confidence: 99%

ADAR1 editing dependency in triple-negative breast cancer

Kung

Cottrell

Ryu

et al. 2020

Preprint

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14Triple-negative breast cancer (TNBC) is the deadliest form of breast cancer. Unlike other 15 types of breast cancer that can be effectively treated by targeted therapies, no such targeted 16 therapy exists for all TNBC patients. The ADAR1 enzyme carries out A-to-I editing of RNA to 17 prevent sensing of cellular double-stranded RNAs (dsRNA). ADAR1 is highly expressed in 18 breast cancer including TNBC. Here, we demonstrate that ADAR1 expression and editing 19 activity is required in TNBC cell lines but not in ER+ and/or Her2+ cells. In TNBC cells, 20 knockdown of ADAR1 attenuates proliferation and tumorigenesis. PKR expression is elevated in 21 TNBC and its activity is induced upon ADAR1-knockdown, which correlates with a decrease in 22 translation. ADAR1-dependent TNBC cell lines also exhibit elevated IFN stimulated gene 23 expression. IFNAR1 reduction significantly rescues the proliferative defects of ADAR1 loss. 24These findings establish ADAR1 as a novel therapeutic target for TNBC tumors. 25 26 Keywords: ADAR1, triple-negative breast cancer, RNA editing, Type I IFN, PKR 27 28 65highlighting the therapeutic potential of ADAR1 inhibitors for the treatment of TNBC. 66 Results 67ADAR1 is highly expressed in all breast cancer subtypes 68 Using publicly available data from TCGA (The Cancer Genome Atlas) (Han et al., 2015, 69 Fumagalli et al., 2015, we found that high expression of ADAR1 correlated with poor prognosis 70 of breast cancers ( Figure 1A). Recent studies indicated that ADAR1 promotes tumorigenesis of 71 metaplastic breast cancers, and that high expression of ADAR1 correlates with poor prognosis in 72 basal-like breast cancers (Sagredo et al., 2018, Dave et al., 2017. Since both basal-like and 73 5 metaplastic breast cancers share similar characteristics with TNBC, we sought to determine the 74 importance of ADAR1 in the tumorigenesis of TNBC. By evaluating the TCGA database, we 75 found that while mRNA expression of ADAR1 was higher in TNBC compared to normal, it was 76 not significantly different between TNBC and non-TNBC tumors ( Figure 1B). Additionally, 77 ADAR1 expression was not significantly higher in any one subtype of breast cancer based on 78 PAM50 classification(Lehmann et al., 2016) (Supplemental Figure 1A). This observation is 79 consistent with data from the Cancer Cell Line Encyclopedia (CCLE), which uses both RNA-seq 80 and Reverse Phase Protein Array (RPPA) to determine RNA and protein expression levels in 81 numerous cancer cell lines (Supplemental Figure 1B-C). Data from both the TCGA and CCLE 82 datasets also revealed that both p150 and p110 isoforms of ADAR1 were expressed at similar 83 levels between TNBC and non-TNBC specimen (Supplemental Figure 1D-H), with p110 84 expression being consistently higher than p150 in all samples. Additionally, we assessed p150 85 isoform expression by immunohistochemistry in TNBC and non-TNBC patient tumors, Figure 86 1D. We sought to determine the protein expression level of the ADAR1-p150 isoform in a panel 87 of established breast ca...

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“…Upon dissemination in a secondary organ, metastatic breast cancer cells (BCCs) can undergo three fates: death, dormancy, or growth. Dormancy does not have a clear biological definition, it has been proposed a classification of dormant phenotypes into cellular dormancy (entering into reversible quiescence in G0) and tumor mass dormancy (a small cluster of cells where proliferation is counterbalanced by apoptosis due to lack of nutrients, blood supply or because of immune surveillance) (Linde et al, 2016;Goddard et al, 2018;Weidenfeld and Barkan, 2018;Lan et al, 2019). However, these states are likely to coexist within the same patients and probably the same cells can dynamically fluctuate between these different states.…”

Section: Metastatic Dormancymentioning

confidence: 99%

“…To distinguish between quiescence and senescence (or even apoptosis), cells must re-enter the proliferative state upon withdrawal of the factors used to trigger dormancy or upon treatment with signals able to drive exit from dormancy. Examples of such signals for BCCs are inflammation (LPS, smoke) (Cock et al, 2016;Albrengues et al, 2018), POSTN , TGFβ1 (Ghajar et al, 2013), RTKs (Tivari et al, 2015;, IL6, Collagen I (Barkan et al, 2010), Src (Barkan et al, 2010;, SFRP2 , IKKβ (Lamiaa et al, 2017), integrins activation (as discussed below); while examples of inhibitors are: TSP1 (Ghajar et al, 2013), p38 (Marlow et al, 2013), Alk5 (Marlow et al, 2013), BMP2 (Gao et al, 2012), TGFβ2 (Bragado et al, 2013), MSK1 (Gawrzak et al, 2018), IFN-β (Lan et al, 2019).…”

Section: Reversible Quiescencementioning

confidence: 99%

In vitro Models of Breast Cancer Metastatic Dormancy

Montagner

2020

Front. Cell Dev. Biol.

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Delayed relapses at distant sites are a common clinical observation for certain types of cancers after removal of primary tumor, such as breast and prostate cancer. This evidence has been explained by postulating a long period during which disseminated cancer cells (DCCs) survive in a foreign environment without developing into overt metastasis. Because of the asymptomatic nature of this phenomenon, isolation, and analysis of disseminated dormant cancer cells from clinically disease-free patients is ethically and technically highly problematic and currently these data are largely limited to the bone marrow. That said, detecting, profiling and treating indolent metastatic lesions before the onset of relapse is the imperative. To overcome this major limitation many laboratories developed in vitro models of the metastatic niche for different organs and different types of cancers. In this review we focus specifically on in vitro models designed to study metastatic dormancy of breast cancer cells (BCCs). We provide an overview of the BCCs employed in the different organotypic systems and address the components of the metastatic microenvironment that have been shown to impact on the dormant phenotype: tissue architecture, stromal cells, biochemical environment, oxygen levels, cell density. A brief description of the organ-specific in vitro models for bone, liver, and lung is provided. Finally, we discuss the strategies employed so far for the validation of the different systems.Keywords: cancer dormancy, metastatic dormancy, in vitro models cancer, cancer metastasis, breast cancer, metastasis biology METASTATIC DORMANCYDormancy is an old concept that describes a clinical phenomenon (Klein, 2011; Uhr and Pantel, 2011), i.e., the relapse of a cancer after surgical removal of the primary tumor in a patient considered clinically disease-free for a long time. This implies that cancer cells disseminated prior to surgery and persisted as Minimal Residual Disease (MRD) for a prolonged time (arbitrarily defined, but usually longer than 5 years) before switching to aggressive growth and overt metastasis. The recurrence can be at the primary site (primary tumor dormancy) or at a secondary site (metastatic dormancy). The mechanisms underlying the two types of dormancy are likely to be partially overlapping if involving cell intrinsic genetic/epigenetic mechanisms, or distinct, if dependent on the tissue microenvironment. Clinical dormancy is common for breast, prostate, melanoma, renal, and thyroid cancers, while it is rarely observed in lung and colon cancers (Uhr and Pantel, 2011). In breast cancers, estrogen receptor (ER) status seems to profoundly influence the rate of relapse: ER− patients tend to recur within the first 5 years following primary tumor diagnosis, while ER+ patients have increased risk between 5 and 20 years (Pan et al., 2017;Pantel and Hayes, 2018). While anti-estrogen therapy significantly improved patient outcomes, a significant fraction of them still

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Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer

Cited by 96 publications

References 51 publications

Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer

Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer

ADAR1 editing dependency in triple-negative breast cancer

In vitro Models of Breast Cancer Metastatic Dormancy

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