CD109 promotes the tumorigenic ability and metastatic motility of pancreatic ductal adenocarcinoma cells

Hatsuzawa, Yuuri; Yamaguchi, Kazunori; Takanashi, Tomoka; Sato, Iwao; Tamai, Keiichi; Mochizuki, Mai; Iwai, Wataru; Wakui, Yuta; Abue, Makoto; Yamamoto, Kuniharu; Yasuda, Jun; Mizuma, Masamichi; Unno, Michiaki; Sugamura, Kazuo

doi:10.1016/j.pan.2020.01.013

Cited by 13 publications

(11 citation statements)

References 29 publications

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“…In our in vitro study, disruption of CD109 expression clearly decreased the migration ability of MIA PaCa-2 cells, which was in line with the results of previous studies [9,13,29,35,36]. In contrast, no apparent effect of CD109 disruption was observed on the migration ability of PANC-1 cells.…”

Section: Discussionsupporting

confidence: 92%

“…Several publications have demonstrated that CD109 expression in tumor cells is associated with progression and prognosis in human malignancy, and our present study results are compatible with their findings [18,19,21,[25][26][27][28][29][30]. Hatsuzawa et al recently reported that CD109 promotes the migration ability of pancreatic cancer cells in vitro, tumorigenesis in a tumor-burden mouse model, and liver metastasis in relapsed ◂ pancreatic cancer, although other clinicopathological characteristics and prognostic significance of CD109 were not observed in their immunohistochemical study performed using clinical materials [35]. Possible reasons why our results of immunohistochemical study were different from their results are as follows: (1) their study included cases with non-curative operation (R1 and R2), but our study excluded cases with non-curative operation, which caused the total number of participants in our study relatively small.…”

Section: Discussionsupporting

confidence: 91%

“…To understand the biological diversity of CD109, it is necessary to study its post-translational modification in detail. In a previous study by Hatsuzawa et al, small interfering RNA (siRNA)-mediated depletion of CD109 led to the inhibition of migration of PANC-1 cells [35]. It is possible that an acute inactivation of CD109 may affect the motility of PANC-1 cells.…”

Section: Discussionmentioning

confidence: 97%

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CD109 expression in tumor cells and stroma correlates with progression and prognosis in pancreatic cancer

et al. 2021

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CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, whose expression is upregulated in some types of malignant tumors. High levels of CD109 in tumor cells have been reported to correlate with poor prognosis; however, significance of CD109 stromal expression in human malignancy has not been elucidated. In this study, we investigated the tumorigenic properties of CD109 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis of 92 PDAC surgical specimens revealed that positive CD109 expression in tumor cells was significantly associated with poor prognosis (disease-free survival, p = 0.003; overall survival, p = 0.002), and was an independent prognostic factor (disease-free survival, p = 0.0173; overall survival, p = 0.0104) in PDAC. Furthermore, CD109 expression was detected in the stroma surrounding tumor cells, similar to that of α-smooth muscle actin, a histological marker of cancer-associated fibroblasts. The stromal CD109 expression significantly correlated with tumor progression in PDAC (TNM stage, p = 0.033; N factor, p = 0.024; lymphatic invasion, p = 0.028). In addition, combined assessment of CD109 in tumor cells and stroma could identify the better prognosis group of patients from the entire patient population. In MIA PaCa-2 PDAC cell line, we demonstrated the involvement of CD109 in tumor cell motility, but not in PANC-1. Taken together, CD109 not only in the tumor cells but also in the stroma is involved in the progression and prognosis of PDAC, and may serve as a useful prognostic marker in PDAC.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 97%

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CD109 expression in tumor cells and stroma correlates with progression and prognosis in pancreatic cancer

et al. 2021

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“…Clinically, CD109 expression is associated with the YAP signature, and coexpression of CD109/YAP renders the worst survival outcome in lung cancer patients. Contrarily, a recent study argued that CD109 suppression did not affect YAP downstream gene expressions in pancreatic ductal adenocarcinoma cells [24]. These findings imply that CD109 may regulate different intracellular mechanisms in a context-dependent manner.…”

Section: Discussionmentioning

confidence: 93%

Upregulation of CD109 Promotes the Epithelial-to-Mesenchymal Transition and Stemness Properties of Lung Adenocarcinomas via Activation of the Hippo-YAP Signaling

Lee

Kuo

Chou

et al. 2020

Cells

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Metastasis is the leading cause of death in lung adenocarcinomas. Identifying potential prognostic biomarkers and exploiting regulatory mechanisms could improve the diagnosis and treatment of lung cancer patients. We previously found that cluster of differentiation 109 (CD109) was upregulated in lung tumor tissues, and CD109 overexpression was correlated with the invasive and metastatic capacities of lung adenocarcinoma cells. However, the contribution of CD109 to lung tumorigenesis remains to be elucidated. In the present study, we identified that CD109 was upregulated in metastatic lung adenocarcinoma cells, and elevation of CD109 was correlated with epithelial-to-mesenchymal transition (EMT) traits in patients with lung adenocarcinoma. Functionally, CD109 expression was crucial for EMT gene expressions, tumor invasiveness, and cancer stemness properties. Moreover, elevation of CD109 was accompanied by upregulation of the yes-associated protein (YAP) signature in metastatic lung cancer cells and lung cancer patients, and activation of YAP was demonstrated to participate in CD109-elicited EMT gene expressions and tumor invasiveness. Our study reveals the molecular mechanism underlying CD109 in lung tumor aggressiveness, and CD109 could be a potential diagnostic and therapeutic target for lung cancer patients.

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“…Cluster of differentiation 109 (CD109) is expressed on primitive hematopoietic stem cells, activated platelets, CD4 + and CD8 + T cells, and keratinocytes (Lin et al, 2002). CD109 is gaining attention as a potential biomarker as it is found highly expressed in several tumors such as squamous cell carcinoma (Hashimoto et al, 2004;Zhang et al, 2005;Hagiwara et al, 2008;Mo et al, 2020), lung cancer (Hashimoto et al, 2004;Sato et al, 2007;Chuang et al, 2017;Taki et al, 2020), pancreatic cancer (Haun et al, 2014;Moffitt et al, 2015;Arias-Pinilla et al, 2018;Hatsuzawa et al, 2020), breast cancer (Tao et al, 2014), glioma (Shiraki et al, 2017;Minata et al, 2019), and many more (Hagikura et al, 2010;Emori et al, 2013Emori et al, , 2015Yokoyama et al, 2017). It has been shown that high expression of CD109 in some of those tumors correlates with a bad outcome for patients (Tao et al, 2014;Emori et al, 2015;Chuang et al, 2017;Yokoyama et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Cell Surface Processing of CD109 by Meprin β Leads to the Release of Soluble Fragments and Reduced Expression on Extracellular Vesicles

Lückstädt¹,

Bub²,

Koudelka³

et al. 2021

Front. Cell Dev. Biol.

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Cluster of differentiation 109 (CD109) is a glycosylphosphatidylinositol (GPI)-anchored protein expressed on primitive hematopoietic stem cells, activated platelets, CD4+ and CD8+ T cells, and keratinocytes. In recent years, CD109 was also associated with different tumor entities and identified as a possible future diagnostic marker linked to reduced patient survival. Also, different cell signaling pathways were proposed as targets for CD109 interference including the TGFβ, JAK-STAT3, YAP/TAZ, and EGFR/AKT/mTOR pathways. Here, we identify the metalloproteinase meprin β to cleave CD109 at the cell surface and thereby induce the release of cleavage fragments of different size. Major cleavage was identified within the bait region of CD109 residing in the middle of the protein. To identify the structural localization of the bait region, homology modeling and single-particle analysis were applied, resulting in a molecular model of membrane-associated CD109, which allows for the localization of the newly identified cleavage sites for meprin β and the previously published cleavage sites for the metalloproteinase bone morphogenetic protein-1 (BMP-1). Full-length CD109 localized on extracellular vesicles (EVs) was also identified as a release mechanism, and we can show that proteolytic cleavage of CD109 at the cell surface reduces the amount of CD109 sorted to EVs. In summary, we identified meprin β as the first membrane-bound protease to cleave CD109 within the bait region, provide a first structural model for CD109, and show that cell surface proteolysis correlates negatively with CD109 released on EVs.

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CD109 promotes the tumorigenic ability and metastatic motility of pancreatic ductal adenocarcinoma cells

Cited by 13 publications

References 29 publications

CD109 expression in tumor cells and stroma correlates with progression and prognosis in pancreatic cancer

CD109 expression in tumor cells and stroma correlates with progression and prognosis in pancreatic cancer

Upregulation of CD109 Promotes the Epithelial-to-Mesenchymal Transition and Stemness Properties of Lung Adenocarcinomas via Activation of the Hippo-YAP Signaling

Cell Surface Processing of CD109 by Meprin β Leads to the Release of Soluble Fragments and Reduced Expression on Extracellular Vesicles

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