Mesenchymal stem cells promote metastasis through activation of an ABL-MMP9 signaling axis in lung cancer cells

Gu, Jie; Hoj, Jacob P.; Rouse, Clay; Pendergast, Ann Marie

doi:10.1371/journal.pone.0241423

Cited by 24 publications

(21 citation statements)

References 48 publications

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“…Preclinical mouse models have shown that genetic or pharmacologic inhibition of the kinases has a greater impact impairing cancer cell metastasis of solid tumors in comparison to primary tumor growth [ 2 , 4 – 6 , 9 , 17 – 19 ]. The predominant effects of the ABL kinases on metastatic phenotypes might be due to cumulative regulation of the epithelial to mesenchymal transition and other distinct steps of the metastatic cascade required for initiation, dissemination and colonization of distal sites [ 115 – 118 ].…”

Section: Abl Kinases In Solid Tumor Progressionmentioning

confidence: 99%

“…Further, lung cancer cells harboring shRNAs against the ABL kinases exhibited decreased extravasation from blood vessels into lung tissue in preclinical mouse models of metastasis [ 4 ]. Recently, ABL kinases were shown to be activated by co-culture of lung adenocarcinoma cells with mesenchymal stem cells (MSCs) leading to ABL-mediated MMP-9 expression, secretion, activation of MMP-9 proteolytic activity and metastasis [ 17 ] (Fig. 2 ).…”

Section: Abl Kinases In Solid Tumor Progressionmentioning

confidence: 99%

“…In this review, we will focus on the role of ABL kinases in regulating downstream targets implicated in EMT as well as distinct cellular processes required for metastatic dissemination. Recent reports have revealed that inhibition of the ABL kinases can decrease tumor outgrowth and impair metastatic spread, indicating the potential use of ABL kinase inhibitors for the treatment of some solid tumors with activated ABL kinases [ 2 , 4 – 6 , 10 , 11 , 17 , 19 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

et al. 2021

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The ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease.

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Section: Abl Kinases In Solid Tumor Progressionmentioning

confidence: 99%

Section: Abl Kinases In Solid Tumor Progressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

et al. 2021

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“…Furthermore, sh‐circ_0058357‐transduced tumors showed reduced levels of circ_0058357 and ABCC1 protein and increased expression of miR‐361‐3p with or without DDP administration (Figure 8(c)–(e)). Our immunohistochemistry analysis also showed a strong reduction in the level of metastasis‐related MMP9 protein 23,24 in sh‐circ_0058357‐transduced tumors with or without DDP administration (Figure 8(e)), suggesting that circ_0058357 depletion may weaken the metastatic potential of the tumors. All these data suggest that downregulation of circ_0058357 expression diminishes tumor growth and enhances DDP sensitivity in vivo.…”

Section: Resultsmentioning

confidence: 74%

Identification of circ_0058357 as a regulator in non‐small cell lung cancer cells resistant to cisplatin by miR‐361‐3p/ABCC1 axis

Chu

et al. 2021

Thoracic Cancer

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Background Drug resistance is a major clinical drawback behind the failure of chemotherapy in non‐small cell lung cancer (NSCLC). In this study, we undertook to identify the precise role of circular RNA (circRNA) circ_0058357 in the functional properties of DDP‐resistant NSCLC cells. Methods Circ_0058357, miR‐361‐3p and ATP‐binding cassette (ABC) subfamily C member 1 (ABCC1) were quantified by qRT‐PCR and western blot. Cell survival and viability were gauged by MTT assay. Cell proliferation, apoptosis, invasion and migration were measured by EdU, flow cytometry, transwell and wound‐healing assays, respectively. The direct relationship between miR‐361‐3p and circ_0058357 or ABCC1 was validated by dual‐luciferase reporter assay. Results Our data showed that circ_0058357 was highly expressed in DDP‐resistant NSCLC tissues and cells. Inhibition of circ_0058357 repressed cell growth, invasion, migration, and promoted DDP sensitivity and cell apoptosis of H1299/DDP and A549/DDP cells in vitro. Moreover, inhibition of circ_0058357 diminished the growth of A549/DDP cells and sensitized them to the cytotoxic effect of DDP in vivo. Mechanistically, circ_0058357 contained a miR‐361‐3p binding site and miR‐361‐3p was identified as a molecular mediator of circ_0058357 regulation. MiR‐361‐3p suppressed ABCC1 expression by binding to ABCC1 3′UTR, and miR‐361‐3p‐mediated inhibition of ABCC1 affected the growth, invasion, migration, apoptosis and DDP sensitivity of H1299/DDP and A549/DDP cells. Furthermore, circ_0058357 regulated ABCC1 expression by competitively binding to shared miR‐361‐3p. Conclusions Our findings identified that inhibition of circ_0058357 suppresses the growth and metastasis of H1299/DDP and A549/DDP cells and sensitizes them to DDP therapy partially by targeting the miR‐361‐3p/ABCC1 axis.

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“…Further on, and indicating biomarker potential of MSC-specific features, plasma levels of these three plasma exosomal microRNAs even showed diagnostic accuracy to discriminate lung cancer patients with or without metastasis [ 38 ]. Addressing the mechanism of how MSCs directly affect the behavior of lung cancer cells was revealed when bone marrow-derived MSCs were shown to promote metastasis through activation of the tyrosine-protein kinase ABL-matrix metalloproteinase 9 (MMP9) signaling axis in a panel of lung cancer cells [ 39 ]. Increased levels of MMP9 in turn were linked to metastasis and reduced survival rates in lung AD patients, strongly suggesting that inhibiting the MSC-NSCLC crosstalk through inhibiting the ABL kinase-MMP9 signaling axis could be a potential target to reduce (MSC-induced) NSCLC metastasis [ 39 ].…”

Section: The Tumor-promoting Action Of Lung Cancer-associated Mscsmentioning

confidence: 99%

Lung-Resident Mesenchymal Stem Cell Fates within Lung Cancer

Sentek

Klein

2021

Cancers

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Lung-resident mesenchymal stem cells (LR-MSCs) are non-hematopoietic multipotent stromal cells that predominately reside adventitial within lung blood vesselss. Based on their self-renewal and differentiation properties, LR-MSCs turned out to be important regulators of normal lung homeostasis. LR-MSCs exert beneficial effects mainly by local secretion of various growth factors and cytokines that in turn foster pulmonary regeneration including suppression of inflammation. At the same time, MSCs derived from various tissues of origins represent the first choice of cells for cell-based therapeutic applications in clinical medicine. Particularly for various acute as well as chronic lung diseases, the therapeutic applications of exogenous MSCs were shown to mediate beneficial effects, hereby improving lung function and survival. In contrast, endogenous MSCs of normal lungs seem not to be sufficient for lung tissue protection or repair following a pathological trigger; LR-MSCs could even contribute to initiation and/or progression of lung diseases, particularly lung cancer because of their inherent tropism to migrate towards primary tumors and metastatic sites. However, the role of endogenous LR-MSCs to be multipotent tumor-associated (stromal) precursors remains to be unraveled. Here, we summarize the recent knowledge how ‘cancer-educated’ LR-MSCs impact on lung cancer with a focus on mesenchymal stem cell fates.

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Mesenchymal stem cells promote metastasis through activation of an ABL-MMP9 signaling axis in lung cancer cells

Cited by 24 publications

References 48 publications

Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

Identification of circ_0058357 as a regulator in non‐small cell lung cancer cells resistant to cisplatin by miR‐361‐3p/ABCC1 axis

Lung-Resident Mesenchymal Stem Cell Fates within Lung Cancer

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