A novel mechanism of plasminogen activation in epithelial and mesenchymal cells

Bydoun, Moamen; Sterea, Andra M.; Weaver, Ian C.G.; Bharadwaj, Alamelu G.; Waisman, David M.

doi:10.1038/s41598-018-32433-y

Cited by 21 publications

(26 citation statements)

References 76 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: 93%

“…We previously observed that plasminogen activation is substantially reduced in p11-depleted cancer cells such as colorectal (14), fibrosarcoma (13), pancreatic (16), and lung (15). We measured plasmin generation in tumor homogenates and cell lines isolated from PyMT tumors and did not observe any difference (Fig 5E and Supporting Fig 3B).…”

Section: Loss Of P11 Does Not Affect Plasminogen Activation (Or Plasmmentioning

confidence: 67%

“…P11, present on the extracellular surface, is complexed with its binding partner annexin A2 (p36). We have reported that p11 regulates plasminogen activation on the cell surface of many cancer cells including fibrosarcoma, colorectal, lung and pancreatic cells (8,(11)(12)(13)(14)(15)(16). We have also reported that p11 regulates the plasmin production of stromal cells including macrophages and endothelial cells (17)(18)(19) and that p11-dependent plasmin generation is necessary for macrophage infiltration to the site of inflammation in subcutaneous tumor growth.…”

Section: Introductionmentioning

confidence: 99%

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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: 93%

Section: Loss Of P11 Does Not Affect Plasminogen Activation (Or Plasmmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Recently, Bydoun et al . revealed the involvement of S100A10 in a novel mechanism of plasminogen activation during the epithelial‐to‐mesenchymal transition (EMT).…”

Section: The Role Of S100a10 As a Plasminogen Receptor In Cancermentioning

confidence: 99%

“…They found that the cells undergoing EMT reciprocally modulate plasminogen activation in part by regulating S100A10 and the plasminogen activation inhibitor (PAI‐1). S100A10 was shown to be upregulated through a SMAD4‐dependent TGFβ1 signaling pathway …”

Section: The Role Of S100a10 As a Plasminogen Receptor In Cancermentioning

confidence: 99%

Multiple functions of S100A10, an important cancer promoter

Saiki

Horii

2019

Pathology International

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The S100 group of calcium binding proteins is composed of 21 members that exhibit tissue/cell specific expressions. These S100 proteins bind a diverse range of targets and regulate multiple cellular processes, including proliferation, migration and differentiation. S100A10, also known as p11, binds mainly to annexin A2 and mediates the conversion of plasminogen to an active protease, plasmin. Higher S100A10 expression has been reported to link to worse outcome and/or chemoresistance in a number of cancer types in lung, breast, ovary, pancreas, gall bladder and colorectum and leukemia although some discrepancy was reported. In this review, we focused on the roles of the S100A10 in cancer. We summarized its biological functions, role in cancer progression, prognostic value and targeting of S100A10 for cancer therapy.

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Global Protease Activity Profiling Identifies HER2-Driven Proteolysis in Breast Cancer

et al. 2021

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Differential expression of extracellular proteases and endogenous protease inhibitors has been associated with distinct molecular subtypes of breast cancer. However, due to the tight post-translational regulation of protease activity, protease expression-level data alone are not sufficient to understand the role of proteases in malignant transformation. Therefore, we hypothesized that global profiles of extracellular protease activity could more completely reflect differences observed at the transcriptional level in breast cancer and that subtype-associated protease activity may be leveraged to identify specific proteases that play a functional role in cancer signaling. Here, we used a global peptide library-based approach to profile the activities of proteases within distinct breast cancer subtypes. Analysis of 3651 total peptide cleavages from a panel of well-characterized breast cancer cell lines demonstrated differences in proteolytic signatures between cell lines. Cell line clustering based on protease cleavages within the peptide library expanded upon the expected classification derived from transcriptional profiling. An isogenic cell line model developed to further interrogate proteolysis in the HER2 subtype revealed a proteolytic signature consistent with activation of TGF-β signaling. Specifically, we determined that a metalloprotease involved in TGF-β signaling, BMP1, was upregulated at both the protein (2-fold, P = 0.001) and activity (P = 0.0599) levels. Inhibition of BMP1 and HER2 suppressed invasion of HER2-expressing cells by 35% (P < 0.0001), compared to 15% (P = 0.0086) observed in cells where only HER2 was inhibited. In summary, through global identification of extracellular proteolysis in breast cancer cell lines, we demonstrate subtype-specific differences in protease activity and elucidate proteolysis associated with HER2-mediated signaling.

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A novel mechanism of plasminogen activation in epithelial and mesenchymal cells

Cited by 21 publications

References 76 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.

Multiple functions of S100A10, an important cancer promoter

Global Protease Activity Profiling Identifies HER2-Driven Proteolysis in Breast Cancer

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