Perinucleolar Compartment Prevalence Has an Independent Prognostic Value for Breast Cancer

Kamath, Rajesh V.; Thor, Ann D.; Wang, Chen; Edgerton, Susan M.; Ślusarczyk, Alicja; Leary, Daniel J.; Wang, J.; Wiley, Elizabeth L.; Jovanović, Bojana; Wu, Qian; Nayar, Ravi; Kovarik, Paula; Shi, Fang; Huang, Sui

doi:10.1158/0008-5472.246.65.1

Cited by 57 publications

(22 citation statements)

References 29 publications

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“…2B) or in cultured PANC1 cells (Fig. 1C), consistent with previous findings that late-stage cancers have higher PNC prevalence (11,12).…”

Section: Metarrestin Suppresses Metastasis and Extends Survival In Mo...supporting

confidence: 91%

“…Thus, complex phenotypic markers that reflect the malignant capacity of cancer cells could potentially be useful to identify effective treatments. PNCs are formed almost exclusively in cancer cells, and their prevalence is closely associated with metastasis in vitro and in vivo, and therefore, they are believed to be such a marker (3,11,12,15). As a multicomponent complex subnuclear body, PNCs may reflect the complex characteristics specific to metastasis better than a single gene or gene product.…”

Section: Discussionmentioning

confidence: 99%

“…To determine whether the preclinical model used retained the features of PNCs observed previously in clinical specimens (11,12), we first measured PNC prevalence in a panel of pancreatic cancer cell lines derived from primary tumors and metastatic lesions from various organs in NSG PANC1 mice. The results showed that PNCs were more numerous in human cancer lineages from a metastatic origin and in metastatic lesions compared to those from primary tumors (Fig.…”

Section: Metarrestin Suppresses Metastasis and Extends Survival In Mo...mentioning

confidence: 99%

“…One such marker is the perinucleolar compartment (PNC) (3), a subnuclear body that is (i) selectively detected in cancer cells but not in normal cells, including embryonic stem cells, (ii) a multicomponent nuclear structure highly enriched with noncoding RNAs and RNA binding proteins (4-6), (iii) a structure associated with chromatin (7), and (iv) involved in RNA metabolism and Pol III function (7)(8)(9)(10). Analyses of cancer cells from different tissues and metastatic lesions demonstrated that PNC prevalence (percentage of nonmitotic cells containing at least one PNC) positively correlates with metastatic potential and disease progression (11,12). High PNC prevalence in primary tumors is associated with poor patient outcomes, including overall survival of patients with breast, colorectal (11,12), and ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Analyses of cancer cells from different tissues and metastatic lesions demonstrated that PNC prevalence (percentage of nonmitotic cells containing at least one PNC) positively correlates with metastatic potential and disease progression (11,12). High PNC prevalence in primary tumors is associated with poor patient outcomes, including overall survival of patients with breast, colorectal (11,12), and ovarian cancer. Thus, being a complex, multicomponent structure, PNC prevalence may better reflect the complex nature of malignant transformation than a single gene or gene product.…”

Section: Introductionmentioning

confidence: 99%

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Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

et al. 2018

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Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinuclear compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, blocks metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Altogether, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.

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“…2B) or in cultured PANC1 cells (Fig. 1C), consistent with previous findings that late-stage cancers have higher PNC prevalence (11,12).…”

Section: Metarrestin Suppresses Metastasis and Extends Survival In Mo...supporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Metarrestin Suppresses Metastasis and Extends Survival In Mo...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

et al. 2018

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Nuclear Domains

2011

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Perinucleolar compartment prevalence is a phenotypic pancancer marker of malignancy

Norton¹,

Pollock²,

Wang³

et al. 2008

Cancer

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BACKGROUND The perinucleolar compartment (PNC) is a subnuclear structure localized at the nucleolar periphery. Previous studies using breast cancer as a model system demonstrated that PNC prevalence (the percentage of cells with 1 or more PNC) increased with disease progression and was associated with poor patient outcomes. METHODS To evaluate the validity of developing PNC prevalence as a novel pan-cancer prognostic marker, the authors investigated whether PNC prevalence was correlated with malignancy in a spectrum of tissue types and evaluated its selective association with malignancy under various experimental conditions. RESULTS PNC prevalence was low in primary and immortalized cells and in cell lines derived from hematologic malignancies, but it was heterogeneous in cell lines derived from solid tumors, including those of epithelial and nonepithelial origins. Studies using human myometrial tissue and thyroid cancer cell lines with various levels of malignancy demonstrated a correlation between high PNC prevalence and malignant potential. Furthermore, PNC prevalence corresponded directly to metastatic capacities in a series of well characterized cell lines of the same origin that were selected for various levels of metastatic capacity in a mouse model. Conversely, PNC prevalence was reduced experimentally by over expressing an antimetastatic protein in breast cancer cells. However, PNC prevalence was not associated with traits that were shared by both cancer and normal cells, including proliferation, glycolysis, and differentiation. CONCLUSIONS Together, these observations helped to verify that PNC prevalence selectively represents malignancy in a broad spectrum of solid tissue tumors, demonstrating its potential to be developed as a pancancer prognostic marker of malignancy.

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Perinucleolar Compartment Prevalence Has an Independent Prognostic Value for Breast Cancer

Cited by 57 publications

References 29 publications

Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

Nuclear Domains

Perinucleolar compartment prevalence is a phenotypic pancancer marker of malignancy

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