5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-β-SMAD4 signaling

Singh, Deepak Kumar; Carcamo, Saul; Farías, Eduardo; Hasson, Dan; Zheng, Wei; Sun, Dan; Huang, Xin; Cheung, Julie F.; Nobre, Ana Rita; Kale, Nupura; Sosa, María Soledad; Bernstein, Emily; Aguirre‐Ghiso, Julio A.

doi:10.1016/j.celrep.2023.112560

Cited by 14 publications

(5 citation statements)

References 62 publications

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“…1 and 2, and patient samples 54,55 that solitary or small cluster of DCCs can co-exist with larger metastatic lesions in the same organ and express dormancy markers. Given that NR2F1 is key regulator of dormancy program in several cancer models 42, 56–58 and we observed that dormant UM population significantly enhance NR2F1 expression. This prompted us to test whether the association of increased NR2F1 in dormant DCCs also holds true in patients’ UM liver metastatic samples by quantifying NR2F1 expression in solitary DCCs or isolated small clusters (surrounding near the metastatic lesion or farther away in the normal liver tissue), metastatic lesion edge and core of metastatic lesion.…”

Section: Resultsmentioning

confidence: 52%

“…NR2F1 a nuclear receptor with only recently identified putative ligands (e.g., sphingolipids) 67 , is a critical regulator of this lineage program and serve a pivotal role in cortical pattering during eye morphogenesis 44,68,69 . Our data identified that among neural crest lineage genes, OMM1.3-QR + dormant UM DCCs upregulate NR2F1 expression, previously linked to dormancy in breast, head and neck squamous, and prostate cancer DCC models 58,70 . This allowed functionally determining that solitary DCCs or small DCC clusters (<8 cells) that enter dormancy must acquire a YAP1 lo /TEAD lo /NR2F1 hi program.…”

Section: Discussionmentioning

confidence: 59%

“…The core of the metastasis was largely NR2F1 negative and anticorrelated with Ki67 detection. It is tempting to speculate that NR2F1 could serve as a marker for dormancy of UM DCCs or in metastasis resected as a treatment option 42, 56–58 .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, as targeted therapies emerge for UM and the Gαq/11 oncogene, it is likely that induction of dormancy might be an expected outcome of such therapies. This may offer an opportunity for maintenance therapies using epigenetic therapies that maintain the NR2F1 program 58 and/or using NR2F1 agonists 56 that maintain its function during or following Gαq/11 inhibitor treatments.…”

Section: Discussionmentioning

confidence: 99%

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Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP signaling in dormant disseminated uveal melanoma

Kadamb,

Anton,

Purwin

et al. 2024

Preprint

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The mechanisms driving late relapse in uveal melanoma (UM) patients remains a medical mystery and major challenge. Clinically it is inferred that UM disseminated cancer cells (DCCs) persist asymptomatic for years-to-decades mainly in the liver before they manifest as symptomatic metastasis. Here we reveal using Gαq/11mut/BAPwt human uveal melanoma models and human UM metastatic samples, that the neural crest lineage commitment nuclear receptor NR2F1 is a key regulator of spontaneous UM DCC dormancy in the liver. Using a quiescence reporter, RNA-seq and multiplex imaging we revealed that rare dormant UM DCCs upregulate NR2F1 expression and genes related to neural crest programs while repressing gene related to cell cycle progression. Gain and loss of function assays showed that NR2F1 silences YAP1/TEAD1 transcription downstream of Gαq/11 signaling and that NR2F1 expression can also be repressed by YAP1. YAP1 expression is repressed by NR2F1 binding to its promoter and changing the histone H3 tail activation marks to repress YAP1 transcription. In vivo CRISPR KO of NR2F1 led dormant UM DCCs to awaken and initiate relentless liver metastatic growth. Cut&Run and bulk RNA sequencing further confirmed that NR2F1 epigenetically stimulates neuron axon guidance and neural lineage programs, and it globally represses gene expression linked to G-protein signaling to drive dormancy. Pharmacological inhibition of Gαq/11mut signaling resulted in NR2F1 upregulation and robust UM growth arrest, which was also achieved using a novel NR2F1 agonist. Our work sheds light on the molecular underpinnings of UM dormancy revealing that transcriptional programs driven by NR2F1 epigenetically short-circuit Gαq/11 signaling to its downstream target YAP1.

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Section: Resultsmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP signaling in dormant disseminated uveal melanoma

Kadamb,

Anton,

Purwin

et al. 2024

Preprint

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show abstract

“…Another interesting and promising direction is the development of drugs aimed at maintaining the dormant DTC phenotype. For example, epigenetic drugs such as azacitidine and retinoic acid, as well as small molecule NR2F1 agonists, can induce DTC dormancy, inhibiting the formation of metastases[ 123 , 124 ].…”

Section: What Can Awaken Dormant Metastases and What Are Possible The...mentioning

confidence: 99%

Colorectal cancer and dormant metastases: Put to sleep or destroy?

Senchukova

2024

World J Gastrointest Oncol

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After reading the review by An et al “Biological factors driving colorectal cancer metastasis”, which covers the problem of the metastasis of colorectal cancer (CRC), I had a desire to discuss with readers one of the exciting problems associated with dormant metastases. Most deaths from CRCs are caused by metastases, which can be detected both at diagnosis of the primary tumor and several years or even decades after treatment. This is because tumor cells that enter the bloodstream can be destroyed by the immune system, cause metastatic growth, or remain dormant for a long time. Dormant tumor cells may not manifest themselves throughout a person’s life or, after some time and under appropriate conditions, may give rise to the growth of metastases. In this editorial, we will discuss the most important features of dormant metastases and the mechanisms of premetastatic niche formation, as well as factors that contribute to the activation of dormant metastases in CRCs. We will pay special attention to the possible mechanisms involved in the formation of circulating tumor cell complexes and the choice of therapeutic strategies that promote the dormancy or destruction of tumor cells in CRCs.

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Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis

Jiao,

Yu,

Zheng

et al. 2024

Clinical & Translational Med

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Tumour cell dormancy is critical for metastasis and resistance to chemoradiotherapy. Polyploid giant cancer cells (PGCCs) with giant or multiple nuclei and high DNA content have the properties of cancer stem cell and single PGCCs can individually generate tumours in immunodeficient mice. PGCCs represent a dormant form of cancer cells that survive harsh tumour conditions and contribute to tumour recurrence. Hypoxic mimics, chemotherapeutics, radiation and cytotoxic traditional Chinese medicines can induce PGCCs formation through endoreduplication and/or cell fusion. After incubation, dormant PGCCs can recover from the treatment and produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric cell division. Additionally, PGCCs can resist hypoxia or chemical stress and have a distinct protein signature that involves chromatin remodelling and cell cycle regulation. Dormant PGCCs form the cellular basis for therapeutic resistance, metastatic cascade and disease recurrence. This review summarises regulatory mechanisms governing dormant cancer cells entry and exit of dormancy, which may be used by PGCCs, and potential therapeutic strategies for targeting PGCCs.

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5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-β-SMAD4 signaling

Cited by 14 publications

References 62 publications

Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP signaling in dormant disseminated uveal melanoma

Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP signaling in dormant disseminated uveal melanoma

Colorectal cancer and dormant metastases: Put to sleep or destroy?

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis

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