Stromal Gas6 promotes the progression of premalignant mammary cells

Gomes, André M. O.; Carron, Emily; Mills, Kylie L.; Dow, Alexa M.; Gray, Zane; Fecca, Christopher R.; Lakey, Meredith A.; Carmeliet, Peter; Kittrell, Frances; Medina, Daniel; Machado, Heather L.

doi:10.1038/s41388-018-0593-5

Cited by 30 publications

(38 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several studies have aimed at macrophage‐derived factors that promote tumor progression in early lesions, confirming the role of macrophages in early cancer invasion (Gomes et al, ). Also, macrophages enhance the influx of cancer cells and induce Ras homolog gene family, member A activity in cancer cells during physical contact (Roh‐Johnson et al, ).…”

Section: Discussionmentioning

confidence: 89%

Three‐dimensional microfluidic tumor–macrophage system for breast cancer cell invasion

Liu

et al. 2019

Biotech & Bioengineering

View full text Add to dashboard Cite

The recrudescence of breast cancer can partly be attributed to poor understanding of the early steps and the mechanisms involved in breast cancer metastasis, especially how tumor inflammatory cells including tumor-associated macrophages (TAM) affect invasion process. However, invasion-related biological studies in traditional in vitro assays or in vivo models are challenging due to the arduousness in establishing models that precisely reproduce the tumor invasion environment. To this end, we proposed a juxtaposed dual-layer cell-loaded hydrogels biomimetic microfluidic system and formed monolayer size-selective permeable vascular endothelial barriers besides the dual layer to mimic mammalian blood vessels. We clarified that in this system, TAM promoted the invasion of breast cancer cells, whereas breast cancer cells maintained the phenotype of TAM cells and promoted the differentiation of U937 cells into TAM. It formed a tumor-macrophage bidirectional crosstalk system. This system could be used for drug screening. So finally, through the calculation of the survival rate of breast cancer cells when cocultured with different macrophages under paclitaxel treatment, we analyzed the antagonism of tumor-macrophage bidirectional crosstalk on anticancer drugs. K E Y W O R D S breast cancer, drug screening, invasion, microfluidic chip, tumor-associated macrophage

show abstract

Section: Discussionmentioning

confidence: 89%

Three‐dimensional microfluidic tumor–macrophage system for breast cancer cell invasion

Liu

et al. 2019

Biotech & Bioengineering

View full text Add to dashboard Cite

show abstract

“…GAS6 (growth arrest‐specific gene 6) is a cytokine and also a ligand for receptor tyrosine kinases, including TYRO3, AXL, and MERTK (TAM), which are well‐known pro‐survival signals in many cancers . In this study, we found that via increasing GAS6 expression, GAS6‐AS2 promoted the secretion of GAS6 in the cell supernatants, and further increased the phosphorylation levels of AXL, AKT, and ERK in an autocrine manner.…”

Section: Discussionmentioning

confidence: 69%

“…Furthermore, GAS6‐AS2 was reported to activate GAS6 expression . GAS6 is a ligand for AXL receptor tyrosine kinase, which further activates downstream pro‐survival signals . Therefore, GAS6 has been revealed to have oncogenic roles in many cancers .…”

Section: Resultsmentioning

confidence: 99%

“…31 GAS6 is a ligand for AXL receptor tyrosine kinase, which further activates downstream prosurvival signals. 33,34 Therefore, GAS6 has been revealed to have oncogenic roles in many cancers. [35][36][37] To assess whether GAS6-AS2 also regulates GAS6 in melanoma, we first detected GAS6 mRNA expression levels in GAS6-AS2 stably overexpressed and depleted melanoma cells.…”

Section: Gas6-as2 Upregulates Gas6 Expression and Activates Axl/aktmentioning

confidence: 99%

See 1 more Smart Citation

Increased expression of long noncoding RNA GAS6‐AS2 promotes proliferation and inhibits apoptosis of melanoma cells via upregulating GAS6 expression

et al. 2019

View full text Add to dashboard Cite

Long noncoding RNAs (lncRNAs) are frequently aberrantly expressed and involved in many cancers, including melanoma. GAS6‐AS2 was a recently identified cancer‐related lncRNA. However, the expression, roles, and functional mechanisms of GAS6‐AS2 in melanoma remain unknown. In this study, we found that lncRNA GAS6‐AS2 is significantly elevated in melanoma tissues and cells. Elevated expression of GAS6‐AS2 is positively correlated with advanced stages and poor prognosis in melanoma. Functional assays demonstrated that ectopic expression of GAS6‐AS2 promotes proliferation and inhibits apoptosis of melanoma cells. In contrast, knockdown of GAS6‐AS2 inhibits proliferation and promotes apoptosis of melanoma cells. Furthermore, in vivo functional assays showed that GAS6‐AS2 promotes melanoma xenograft growth. Mechanistically, we found that GAS6‐AS2 upregulates GAS6 expression, promotes GAS6 secretion, and activates AXL/AKT/ERK signals. The expression of GAS6 was positively correlated with that of GAS6‐AS2 in melanoma tissues. In addition, deficiency of GAS6 reverses the biological roles of GAS6‐AS2 overexpression in melanoma cell proliferation and apoptosis. Collectively, our data identified GAS6‐AS2 as an oncogenic lncRNA in melanoma via activation of GAS6/AXL/AKT/ERK signals. Our data suggested that GAS6‐AS2 may be a novel potential prognostic biomarker and therapeutic target for melanoma.

show abstract

“…Gas6 is a multifunctional protein that is secreted by different cell types. Gas6 has been shown to be produced by macrophages in pre-malignant lesions of a mammary tumor model [28] and in xenograft and orthotopic models of colon and pancreatic cancer [29]. Gas6 can also be produced by tumor cells [30] and fibroblasts [31].…”

Section: Resultsmentioning

confidence: 99%

Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits pancreatic cancer metastasis

Mielgo

Ireland

Luckett

et al. 2019

Preprint

View full text Add to dashboard Cite

Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits 2 pancreatic cancer metastasis. 3 Running title 4Gas6 blockade prevents pancreatic cancer metastasis 5 6 Growth arrest-specific gene 6 (Gas6) is a multifunctional factor that regulates several 50 processes in normal physiology and pathophysiology [1].Gas6 binds to the Tyro3, 51 Axl and Mer (TAM) family of receptor tyrosine kinases (TAM receptors) with the 52 highest affinity for Axl [2]. Gas6 supports erythropoiesis, platelet aggregation, 53 angiogenesis, efferocytosis, and inhibits the immune response [3]. Gas6 is critical for 54 the maintenance of immune homeostasis and mice deficient in Gas6 or TAM 55 receptors experience severe autoimmune diseases [4]. Gas6 and its main receptor 56 Axl are overexpressed in several cancer types including, breast, ovarian, gastric, 57 glioblastoma, lung and pancreatic cancer and their expression correlates with a poor 58 prognosis [5]. Axl is ubiquitously expressed in all tissues [6] but is particularly notable 59 in cancer cells, macrophages, dendritic cells and natural killer cells for its role in 60 driving immunosuppression and tumor progression [7-9]. Several cancer studies 61 have focused on the role of Gas6-Axl signaling on the tumor cells and have 62 demonstrated that Axl activation supports tumor cells proliferation, epithelial-63 mesenchymal transition (EMT), drug resistance, migration and metastasis [5]. 64 Factors secreted within the tumor microenvironment are able to sustain Gas6/Axl 65 signaling. Hypoxia Inducible Factor (HIF) has been shown to bind to the Axl 66 promoter region and upregulate its expression on renal cell carcinoma cells [10]. 67 Secretion of IL-10 and M-CSF by tumor cells induces tumor associated 68 macrophages to secrete Gas6 [11].69However, only a few studies have investigated the role of Gas6-Axl signaling in the 70 immune response to breast cancer, ovarian cancer and melanoma [7, 9]. 71 4In solid tumors such as breast or pancreatic cancer, the tumor stroma can represent 72 up to 80% of the tumor mass and actively influences cancer progression, metastasis 73 [12][13][14] and resistance to therapies [15][16][17]. 74 Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers 75 worldwide and better therapies are urgently needed [18]. Metastasis, therapy 76 resistance, and immunosuppression are key characteristics of pancreatic tumors [19, 77 20]. The Gas6-Axl pathway is activated in 70% of pancreatic cancer patients [21] 78 and is associated with a poor prognosis and increased frequency of distant 79 metastasis [22]. Blocking Gas6 or its receptor Axl inhibits cancer progression [23, 24] 80 and several Axl inhibitors are currently being tested in cancer patients, including 81 PDA patients. While the cancer cell autonomous functions of Gas6 are well 82 documented, the effect of Gas6 signaling in the stroma/immune compartment in 83 pancreatic cancer has not been fully explored. In these studies, we sought to 84 understand the effect of Gas6 bloc...

show abstract

Stromal Gas6 promotes the progression of premalignant mammary cells

Cited by 30 publications

References 54 publications

Three‐dimensional microfluidic tumor–macrophage system for breast cancer cell invasion

Three‐dimensional microfluidic tumor–macrophage system for breast cancer cell invasion

Increased expression of long noncoding RNA GAS6‐AS2 promotes proliferation and inhibits apoptosis of melanoma cells via upregulating GAS6 expression

Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits pancreatic cancer metastasis

Contact Info

Product

Resources

About