EFEMP1 binds to STEAP1 to promote osteosarcoma proliferation and invasion via the Wnt/β-catenin and TGF-β/Smad2/3 signal pathways

Zhang, Dong; Han, Shasha; Pan, Xin; Li, Hao; Zhao, Hua; Gao, Xianlei; Wang, Songgang

doi:10.1016/j.jbo.2022.100458

Cited by 7 publications

(4 citation statements)

References 33 publications

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“…As already mentioned, EFEMP1 plays a central role in maintaining the structural integrity of the ECM, organizing the ECM scaffold and in promoting cell-ECM adhesion in normal connective tissue and disease [ 88 ]. This protein is upregulated in some tumours and has been described as a novel soluble signal strongly associated with the malignant progression in gliomas, pancreatic, ovarian, and bladder cancer, as well as OS, by promoting cell proliferation, MMP-induced invasion, migration, EMT, and angiogenesis [ 89 – 93 ]. Although not explored, we reasoned that EFEMP1 is involved in ECM remodelling and/or contributes to cell-matrix adhesion, which are integral parts of the premetastatic process, as previously observed in our study.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling

Almeida,

Santos,

Sampaio-Ribeiro

et al. 2023

J Exp Clin Cancer Res

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Background Lung metastasis is the most adverse clinical factor and remains the leading cause of osteosarcoma-related death. Deciphering the mechanisms driving metastatic spread is crucial for finding open therapeutic windows for successful organ-specific interventions that may halt or prevent lung metastasis. Methods We employed a mouse premetastatic lung-based multi-omics integrative approach combined with clinical features to uncover the specific changes that precede lung metastasis formation and identify novel molecular targets and biomarker of clinical utility that enable the design of novel therapeutic strategies. Results We found that osteosarcoma-bearing mice or those preconditioned with the osteosarcoma cell secretome harbour profound lung structural alterations with airway damage, inflammation, neutrophil infiltration, and extracellular matrix remodelling with increased deposition of fibronectin and collagens by resident stromal activated fibroblasts, favouring the adhesion of disseminated tumour cells. Systemic-induced microenvironmental changes, supported by transcriptomic and histological data, promoted and accelerated lung metastasis formation. Comparative proteome profiling of the cell secretome and mouse plasma identified a large number of proteins involved in extracellular-matrix organization, cell-matrix adhesion, neutrophil degranulation, and cytokine-mediated signalling, consistent with the observed lung microenvironmental changes. Moreover, we identified EFEMP1, an extracellular matrix glycoprotein exclusively secreted by metastatic cells, in the plasma of mice bearing a primary tumour and in biopsy specimens from osteosarcoma patients with poorer overall survival. Depletion of EFEMP1 from the secretome prevents the formation of lung metastasis. Conclusions Integration of our data uncovers neutrophil infiltration and the functional contribution of stromal-activated fibroblasts in ECM remodelling for tumour cell attachment as early pro-metastatic events, which may hold therapeutic potential in preventing or slowing the metastatic spread. Moreover, we identified EFEMP1, a secreted glycoprotein, as a metastatic driver and a potential candidate prognostic biomarker for lung metastasis in osteosarcoma patients. Graphical abstract Osteosarcoma-derived secreted factors systemically reprogrammed the lung microenvironment and fostered a growth-permissive niche for incoming disseminated cells to survive and outgrow into overt metastasis. Daily administration of osteosarcoma cell secretome mimics the systemic release of tumour-secreted factors of a growing tumour in mice during PMN formation; Transcriptomic and histological analysis of premetastatic lungs revealed inflammatory-induced stromal fibroblast activation, neutrophil infiltration, and ECM remodelling as early onset pro-metastatic events; Proteome profiling identified EFEMP1, an extracellular secreted glycoprotein, as a potential predictive biomarker for lung metastasis and poor prognosis in osteosarcoma patients. Osteosarcoma patients with EFEMP1 expressing biopsies have a poorer overall survival.

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Section: Discussionmentioning

confidence: 99%

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling

Almeida,

Santos,

Sampaio-Ribeiro

et al. 2023

J Exp Clin Cancer Res

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“…EFEMP1 is an ECM glycoprotein involved in organizing the ECM scaffold and promoting cell-cell and cell-ECM adhesion in normal connective tissues and disease (Timpl et al, 2003). This glycoprotein is involved in the carcinogenesis of some tumours, including gliomas, pancreatic, ovarian, or bladder cancer, as well as OS, by promoting cell proliferation, MMPinduced invasion, migration, EMT, and angiogenesis (Al Khader et al, 2022;Chen et al, 2021;Hu et al, 2009;Zhang et al, 2022). In a previous study, Wang et al (Wang et al, 2015) found higher levels of EFEMP1 in the serum of OS patients compared to healthy individuals, which led them to speculate a possible link between EFEMP1 and the progression of the disease.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling

Almeida

Santos

Ribeiro

et al. 2023

Preprint

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Lung metastasis represents the leading cause of osteosarcoma-related death. Progress in preventing lung metastasis is pretty modest due to the inherent complexity of the metastatic process and the lack of suitable models. Herein, we provide mechanistic insights into how osteosarcoma systemically reprograms the lung microenvironment for metastatic outgrowth using metastatic mouse models and a multi-omics approach. We found that osteosarcoma-bearing mice or those preconditioned with cell-secretome harbour profound lung structural alteration with airways damage, inflammation, neutrophil infiltration, and remodelling of the extracellular matrix with deposition of fibronectin and collagen by stromal activated fibroblasts for tumour cell adhesion. These changes, supported by transcriptomic and histological data, promoted and accelerated the development of lung metastasis. Comparative proteome profiling of the cell secretome and mouse plasma identified a large number of proteins engaged in the extracellular-matrix organization, cell-matrix adhesion, neutrophil degranulation, and cytokine-mediated signalling, which were consistent with the observed lung microenvironmental changes. Moreover, we identified EFEMP1, a secreted extracellular matrix glycoprotein, as a potential risk factor for lung metastasis and a poor prognosis factor in osteosarcoma patients.

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“…[54] Numerous studies have shown that propagation and survival of OS cells are also closely related to the TGF-β/Smad signaling pathway. [55][56][57][58][59] For example, Lamora et al [60] found that overexpressed Smad7 affected the "vicious cycle" established between tumor cells and OS through its ability to reduce OS activity, while over-expressed Smad7 in OS cells can also inhibit primary tumor metastasis to the lung in SD208 mice.…”

Section: Tgf-β/smad Signaling Pathwaymentioning

confidence: 99%

Effect of traditional Chinese medicine in osteosarcoma: Cross-interference of signaling pathways and potential therapeutic targets

Liu,

Jiang,

et al. 2024

Medicine

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Osteosarcoma (OS) has a high recurrence rate, disability rate, mortality and metastasis, it brings great economic burden and psychological pressure to patients, and then seriously affects the quality of life of patients. At present, the treatment methods of OS mainly include radiotherapy, chemotherapy, surgical therapy and neoadjuvant chemotherapy combined with limb salvage surgery. These treatment methods can relieve the clinical symptoms of patients to a certain extent, and also effectively reduce the disability rate, mortality and recurrence rate of OS patients. However, because metastasis of tumor cells leads to new complications, and OS cells become resistant with prolonged drug intervention, which reduces the sensitivity of OS cells to drugs, these treatments still have some limitations. More and more studies have shown that traditional Chinese medicine (TCM) has the characteristics of “multiple targets and multiple pathways,” and can play an important role in the development of OS through several key signaling pathways, including PI3K/AKT, Wnt/β-catenin, tyrosine kinase/transcription factor 3 (JAK/STAT3), Notch, transforming growth factor-β (TGF-β)/Smad, nuclear transcription factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), nuclear factor E2-related factor 2 (Nrf2), Hippo/YAP, OPG/RANK/RANKL, Hedgehog and so on. In this paper, the signaling pathways of cross-interference between active ingredients of TCM and OS were reviewed, and the development status of novel OS treatment was analyzed. The active ingredients in TCM can provide therapeutic benefits to patients by targeting the activity of signaling pathways. In addition, potential strategies for targeted therapy of OS by using ferroptosis were discussed. We hope to provide a unique insight for the in-depth research and clinical application of TCM in the fields of OS growth, metastasis and chemotherapy resistance by understanding the signaling crosstalk between active ingredients in TCM and OS.

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EFEMP1 binds to STEAP1 to promote osteosarcoma proliferation and invasion via the Wnt/β-catenin and TGF-β/Smad2/3 signal pathways

Cited by 7 publications

References 33 publications

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling

Effect of traditional Chinese medicine in osteosarcoma: Cross-interference of signaling pathways and potential therapeutic targets

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