Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10

Madureira, Patrícia A.; Bharadwaj, Alamelu G.; Bydoun, Moamen; Garant, Katy; O’Connell, Paul A.; Lee, Patrick; Waisman, David M.

doi:10.18632/oncotarget.10279

Cited by 23 publications

(37 citation statements)

References 83 publications

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“…We have previously reported that p11 is responsible for majority of the plasmin generation in various cancer cell lines (5,15,16,44). However, in the present study we were unable to detect any differences in plasmin generation between cancer cells or tumor homogenates isolated from the PyMT/p11-KO and PyMT/p11-WT mice.…”

Section: Discussioncontrasting

confidence: 92%

S100A10 has a Critical Regulatory Function in Mammary Tumor Growth and Metastasis: Insights using MMTV-PyMT Oncomice and Clinical Patient Sample Analysis.

Bharadwaj

Dahn

Liu

et al. 2020

Preprint

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Background: Breast cancer is one of the leading causes of cancer deaths in women worldwide. Significant advances have been made in the diagnosis and treatment of breast cancer, treatment of triple-negative and metastatic breast cancer poses significant challenge. Metastasis is a multi-step cascade that involves activation of proteases such as plasmin to facilitate the invasive escape of tumor cells to distant organs. The rate-limiting step in plasmin generation requires the interaction of plasminogen with cell surface plasminogen binding sites. Our laboratory first demonstrated that the plasminogen receptor, S100A10 (p11) was upregulated in many cancer cells and was responsible for much of their plasmin generation. Recently, it was reported that p11 is one of a few genes that are activated when human breast cancer cells metastasize from the primary tumor into the blood and is upregulated during the conversion of breast cancer cells to invasive phenotype. In the current study we have investigated the role of p11 in breast cancer tumor progression.Methods: We have used MMTV-PyMT a mouse transgenic mammary tumor model to investigate the effects of loss of p11 on spontaneous tumor initiation, growth and progression to invasive carcinoma and metastasis. We used experimental metastasis assays to ascertain the role of stromal p11 in tumor cell extravasation and lung colonization. Genes and cytokines regulated by p11 in the PyMT tumors were assessed by microarray analysis and RT-qPCR. Finally, we employed gene profiling analysis and immunohistochemical staining of breast cancer patient tumors to correlate p11 expression to human breast cancer progression. Results: Genetic deletion of p11 resulted in significantly decreased tumor onset, growth rate, and spontaneous pulmonary metastatic burden in the PyMT/p11-KO mice. This phenotype was accompanied by substantial reduction in Ki67 positivity, macrophage infiltration, decreased vascular density in the primary tumors and decrease in invasive carcinoma and pulmonary metastasis. Surprisingly, immunohistochemical analysis of wild-type MMTV-PyMT mice failed to detect p11 expression in the tumors or metastatic tumor cells and loss of p11 did not decrease plasmin generation in the PyMT tumors and cells. Furthermore, tumor cells expressing p11 displayed dramatically reduced lung metastasis when injected into p11-depleted mice, further strengthening the stromal role of p11 in tumor growth and metastasis. Transcriptome analysis of the PyMT tumors from p11-KO mice showed marked reduction in genes involved in breast cancer development, progression, and inflammation such as AREG, MUC1 and S100A8. The PyMT/p11- KO tumors displayed a remarkable increase in inflammatory cytokines such as IL-6, IL-10 and IFN-γ. Gene expression profiling from 176 primary breast cancer samples obtained through the CBCF tumor bank showed that p11 mRNA levels were significantly higher in tumors compared to normal tissues. P11 mRNA expression was significantly associated with poor patient prognosis (hazard ratio – 3.34) and significantly elevated in high grade, triple negative (TN) tumors, and tumors with high proliferative index. Evaluation of p11 protein expression in a NSHA cohort of patients revealed substantial upregulation of p11 in cancer tissues compared to normal controls. Conclusions: This is the first study demonstrating the crucial role of p11 in breast tumor development and metastasis. The results emphasize the potential of p11 as a diagnostic and prognostic biomarker in breast cancer.

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Section: Discussioncontrasting

confidence: 92%

S100A10 has a Critical Regulatory Function in Mammary Tumor Growth and Metastasis: Insights using MMTV-PyMT Oncomice and Clinical Patient Sample Analysis.

Bharadwaj

Dahn

Liu

et al. 2020

Preprint

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“…This is supported by our recent findings which showed that S100A10 is driven by the RAS family of proteins in HEK293 cells via the RalGDS signaling arm. S100A10 enhanced Ras‐mediated plasminogen activation and was important for plasminogen‐dependent Ras‐induced invasion of HEK293 cells (Madureira et al ., ). Notably, the ACA treatment of iKRAS cells abolished plasminogen activation in the absence and presence of induced KRAS G12D expression.…”

Section: Discussionmentioning

confidence: 97%

S100A10, a novel biomarker in pancreatic ductal adenocarcinoma

et al. 2018

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Pancreatic cancer is arguably the deadliest cancer type. The efficacy of current therapies is often hindered by the inability to predict patient outcome. As such, the development of tools for early detection and risk prediction is key for improving outcome and quality of life. Here, we introduce the plasminogen receptor S100A10 as a novel predictive biomarker and a driver of pancreatic tumor growth and invasion. We demonstrated that S100A10 mRNA and protein are overexpressed in human pancreatic tumors compared to normal ducts and nonductal stroma. S100A10 mRNA and methylation status were predictive of overall survival and recurrence‐free survival across multiple patient cohorts. S100A10 expression was driven by promoter methylation and the oncogene KRAS. S100A10 knockdown reduced surface plasminogen activation, invasiveness, and in vivo growth of pancreatic cancer cell lines. These findings delineate the clinical and functional contribution of S100A10 as a biomarker in pancreatic cancer.

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“…Congruously, the tumor cells with Ras transformation display a substantial reduction or a loss in the generation of plasmin in the absence of S100A10. The invasiveness of tumor cells sharply decreases in the absence or depletion of S100A10 induced by the reduction of Ras [55].…”

Section: S100a10 Cooperates With Ras To Regulate Tumor Developmentmentioning

confidence: 99%

“…Furthermore, plasmin is suggested to simultaneously stimulate the pro-MMP-1, 3, 7, 9, 10, and 13 that result in the generation of their corresponding MMPs. These proteases promote the invasiveness of tumor cells by degrading and passing through extracellular matrix as well as the basement membrane [55,56]. The expression levels of the members of the plasminogen receptors, such as S100A10 [14], S100A4, cytokeratin 8 [57], and enolase-1 [58] could be influenced by Ras directly.…”

Section: S100a10 Cooperates With Ras To Regulate Tumor Developmentmentioning

confidence: 99%

“…Intracellular RAS can increase the transcription and expression of S100A10. The S100A10 and annexin A2 form the S100A10-annexin A2 heterotetramer complex, which is transported to the cell surface via caveola to promote the production of plasmin which plays a key role in Ras-dependent cell invasiveness [55]. Congruously, the tumor cells with Ras transformation display a substantial reduction or a loss in the generation of plasmin in the absence of S100A10.…”

Section: S100a10 Cooperates With Ras To Regulate Tumor Developmentmentioning

confidence: 99%

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Critical role and its underlying molecular events of the plasminogen receptor, S100A10 in malignant tumor and non-tumor diseases

Li¹,

Ma²,

Fei³

et al. 2020

J. Cancer

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S100A10 is a small molecular weight protein expressed in the cytoplasm of many cells and one of the members of the S100 protein family that binds calcium and forms the largest subgroup of EF-hand proteins. The regulatory processes of S100A10 are complicated. S100A10 participates in the regulation of a variety of tumor and non-tumor diseases through cascade reactions with multitudinous signaling molecules. In malignant tumors, such as acute promyelocytic leukemia (APL) and lung cancer, S100A10 is likely involved in their progression, including invasion and metastasis through the regulation of plasmin production and subsequent plasmin-dependent stimulation of other proteases, such as matrix metalloproteinase (MMP)-2 and -9. Both the plasmin and MMPs are capable of inducing degradation of the extracellular matrix (ECM) and basement membrane, which is a critical step for tumor progression. In non-tumor diseases, the distribution of S100A10 in the brain and its interaction with 5-hydroxytryptamine 1B (5-HT1B) receptor, an important mediator in the central nervous system that maintains a dynamic balance of the neurotransmitters, correlates with depression-like behavior. S100A10 also participates in inflammatory responses through the regulation of peripheral macrophage migration to the inflammatory sites, which depends on the generation of plasmin and other proteinases at the surface of macrophages. Considerable attention should be paid to understand the significant role of S100A10 in the modulation of malignant tumor and non-tumor diseases.

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Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10

Cited by 23 publications

References 83 publications

S100A10 has a Critical Regulatory Function in Mammary Tumor Growth and Metastasis: Insights using MMTV-PyMT Oncomice and Clinical Patient Sample Analysis.

S100A10 has a Critical Regulatory Function in Mammary Tumor Growth and Metastasis: Insights using MMTV-PyMT Oncomice and Clinical Patient Sample Analysis.

S100A10, a novel biomarker in pancreatic ductal adenocarcinoma

Critical role and its underlying molecular events of the plasminogen receptor, S100A10 in malignant tumor and non-tumor diseases

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