A brain-enriched lncRNA shields cancer cells from immune-mediated killing for metastatic colonization in the brain

Liu, Weiguang; Sun, Peng; Xia, Lingling; He, Xilin; Xia, Zhengmiao; Huang, Yehong; Liu, Wenzhuo; Li, Lulu; Chen, Liming

doi:10.1073/pnas.2200230119

Cited by 8 publications

(5 citation statements)

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“…Brain parenchyma limits cancer cell invasion and survival through the protein plasmin, that DTCs counteract by secreting serpin proteins to initiate their colonization ( 155 ). The lncRNA BMOR has also been reported to promote breast cancer cell brain colonization, possibly through evasion of immune clearance ( 159 ). Two recent reports have addressed the role of dormancy in this process.…”

Section: Station 3: At the Metastatic Niche The Final Stage On The Roadmentioning

confidence: 99%

Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)

et al. 2022

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Multiple factors act in concert to define the fate of disseminated tumor cells (DTCs) to enter dormancy or develop overt metastases. Here, we review these factors in the context of three stages of the metastatic cascade that impact DTCs. First, cells can be programmed within the primary tumor microenvironment to promote or inhibit dissemination, and the primary tumor can condition a premetastatic niche. Then, cancer cells from the primary tumor spread through hematogenous and lymphatic routes, and the primary tumor sends cues systematically to regulate the fate of DTCs. Finally, DTCs home to their metastatic site, where they are influenced by various organ-specific aspects of the new microenvironment. We discuss these factors in the context of breast cancer, where about one third of patients develop metastatic relapse. Finally, we discuss how the standard-of-care options for breast cancer might affect the fate of DTCs.

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Section: Station 3: At the Metastatic Niche The Final Stage On The Roadmentioning

confidence: 99%

Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)

et al. 2022

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“…lncRNA can regulate gene expression via chromatin modification, transcriptional, or post-transcriptional modifications and consequently impacts a variety of molecular targets . This property allows one lncRNA to have regulatory control across multiple levels, but it can be dysregulated in a tissue- and disease-specific manner. − Differentiation antagonizing noncoding RNA (DANCR) is an oncogenic lncRNA overexpressed in triple negative breast cancer (TNBC), an aggressive breast cancer subtype that lacks expression of hormone receptors and suitable drug targets. DANCR is known to increase cell proliferation and invasion in TNBC. − Because lncRNA is considered as an undruggable target for conventional therapeutics, RNA interference (RNAi) with small interfering RNA (siRNA) is an effective approach for regulating lncRNA for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Evaluating Dual-Targeted ECO/siRNA Nanoparticles against an Oncogenic lncRNA for Triple Negative Breast Cancer Therapy with Magnetic Resonance Molecular Imaging

Nicolescu

Schilb

Kim

et al. 2023

Chemical & Biomedical Imaging

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Differentiation antagonizing noncoding RNA (DANCR) is recognized as an oncogenic long noncoding RNA (lncRNA) overexpressed in triple negative breast cancer (TNBC). We showed in a previous study that RNAi with targeted multifunctional ionizable lipid ECO/siRNA nanoparticles was effective to regulate this undruggable target for effective treatment of TNBC. In this study, we developed dual-targeted ECO/siDANCR nanoparticles by targeting a tumor extracellular matrix oncoprotein, extradomain B fibronectin (EDB-FN), and integrins overexpressed on cancer cells for enhanced delivery of siDANCR. The treatment of Hs578T TNBC cells and MCF-7 estrogen receptor-positive cells in vitro resulted in significant down-regulation of DANCR and EDB-FN and suppressed invasion and 3D spheroid formation of the cells. Magnetic resonance molecular imaging (MRMI) with an EDB-FN-targeted contrast agent, MT218, was used to noninvasively evaluate tumor response to treatment with the targeted ECO/siDANCR nanoparticles in female nude mice bearing orthotopic Hs578T and MCF-7 xenografts. MRMI with MT218 was effective to differentiate between aggressive TNBC with high DANCR and EDB-FN expression and ER+ MCF-7 tumors with low expression of the targets. MRMI showed that the dual-targeted ECO/siDANCR nanoparticles resulted in more significant inhibition of tumor growth in both models than the controls and significantly reduced EDB-FN expression in the TNBC tumors. The combination of MRMI and dual-targeted ECO/siDANCR nanoparticles is a promising approach for image-guided treatment of TNBC by regulating the onco-lncRNA.

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“…The immune system is a highly sophisticated system that is a complex network of organs, immune cells, non-immune cells and proteins, where increasing studies have noticed essential roles of immune modulation by non-immune cells (Dainichi et al, 2021). For example, we recently reported that breast cancer cells, as non-immune cells, facilitate the formation of an immunosuppressive microenvironment via cancer-intrinsic BOMR-inhibited IRF3 (Liu et al, 2022). However, the function of GATA3 in the regulation of immunity in non-immune cells remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

GATA3 ZnF2-defective mutant condensation underlies type I IFN-activating in breast cancer

Chen

Wan

Pei

et al. 2023

Preprint

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Zinc finger (ZnF) transcription factors (TFs) consist of ZnF-containing DNA-binding domains (DBDs) and intrinsically disordered region (IDR)-containing activation domains (ADs). Recent studies suggest that liquid-liquid phase separation (LLPS) is the fundamental mechanism underlying human health and disease, with ZnF TFs activating gene expression through the LLPS capacity of their IDR-containing ADs. However, little is known about how the well-folded DBD of ZnF TFs might be involved in their LLPS mechanism. GATA3 has been identified as one of the most frequently mutated genes in breast cancer, and its encoded protein GATA3, which contains two ZnFs (ZnF1 and ZnF2) in its DBD, is a master regulator of immunity. Here, we show that GATA3 undergoes LLPS in cells and in vitro, with its DBD playing an important regulatory role. Mechanistically, ZnF2 in the DBD contains two arginine amino acids (R329 and R330) to provide the critical charges to regulate GATA3 LLPS by generating multivalent electrostatic interactions. Functionally, we demonstrated that ZnF2-regulated GATA3 LLPS is the mechanism underlying the multifaceted function of GATA3 in breast cancer development and immune regulation, where aberrant GATA3 LLPS caused by artificial or breast cancer-associated ZnF2-defective mutations showed significantly reduced potentials in promoting breast cancer development and exhibited remarkably enhanced capacities in activating type I interferon signaling. Since ZnF is a common feature in the DBDs of ZnF TFs, by describing GATA3 as a proof-of-principle, our data suggest that ZnF-regulated LLPS may be a general mechanism underlying the multifaceted function of ZnF TFs in human health and disease.

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A brain-enriched lncRNA shields cancer cells from immune-mediated killing for metastatic colonization in the brain

Cited by 8 publications

References 50 publications

Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)

Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)

Evaluating Dual-Targeted ECO/siRNA Nanoparticles against an Oncogenic lncRNA for Triple Negative Breast Cancer Therapy with Magnetic Resonance Molecular Imaging

GATA3 ZnF2-defective mutant condensation underlies type I IFN-activating in breast cancer

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