A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer

Astudillo, Pablo

doi:10.3389/fcell.2021.633675

Cited by 6 publications

(6 citation statements)

References 78 publications

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“…A flow cytometry-based analysis validated this finding at the protein level (Figure 1b). However, previous reports indicate that the cognate WNT5A receptor ROR2 is downregulated in gastric cancer cells (Astudillo, 2021, Yan et al, 2016. Therefore, the primary aim of this study was to further investigate the distribution of WNT5A receptors in a gastric tumor to understand how gastric cancer cells respond to a WNT5A-high environment.…”

Section: Resultsmentioning

confidence: 98%

“…However, the identity of the receptor for WNT5A on gastric cancer cells remained unclear, given that ROR2 is commonly down-regulated in these tumors (Astudillo, 2021, Yan et al, 2016). Here, we show that in addition to WNT5A, ROR2 is also upregulated on both pancreatic and gastric cancer-associated fibroblasts compared to the gastric cancer cell line, AGS, and normal gastric fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

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Cancer-associated fibroblast-derived ROR2 induces WNT/PCP activation and polarized migration in receiving gastric cancer cells

Rogers

Zhang

Anagnostidis

et al. 2022

Preprint

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Bone marrow-derived mesenchymal stem cells and cancer-associated fibroblasts in the tumor-stromal environment have been linked to cancer progression in many studies. These fibroblasts provide signaling factors to the tumor cells that promote proliferation, survival, invasion, and metastasis. One signaling pathway influencing tumor cell behavior is the WNT/Planar Cell Polarity (PCP) signaling in gastric cancer. Here, we show that the gastric tumor cell line, AGS, can respond to the PCP ligand WNT5A, however, express a very low level of the bona-fide WNT/PCP receptor, ROR2. At the same time, we find that CAF display long filopodia and had significantly higher levels of ROR2 than normal gastric fibroblasts. By high-resolution imaging, we observe a direct, cytoneme-mediated transfer of a complex containing ROR2 and WNT5A from CAF to the gastric cancer cells. The amount of ROR2 transferred correlated with JNK signaling in receiving cells, showing a direct requirement for receptor transfer. Co-culture of AGS with CAF expressing a dominant-negative form of ROR2 exhibited reduced actin polarization and migration compared to wild-type CAF. Furthermore, induction of migration via paracrine ROR2 transfer was observed in a zebrafish in vivo model. These unexpected findings demonstrate a fresh role in the direct transfer of a Wnt receptor from a signal-producing cell to a receiving cell and explain the mechanism by which gastric cancer cells expressing low levels of ROR2 can respond to a WNT5A-high tumor microenvironment.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Cancer-associated fibroblast-derived ROR2 induces WNT/PCP activation and polarized migration in receiving gastric cancer cells

Rogers

Zhang

Anagnostidis

et al. 2022

Preprint

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“…Further, the positive association between the scores for exosome secretion, TGF-β signaling, and EMT suggests a cooperation between sEV secretion and TGF-β signaling to drive cancer progression, which was further confirmed in vitro and in vivo. In combination with further research on the intracellular effectors controlling EV biogenesis, the association between alterations in EV secretion and molecular signatures for other EMT-related pathways 45 , 46 can also be explored. A deeper understanding of the crosstalk between multiple signaling pathways may help us to more accurately determine molecular drivers promoting disease progression.…”

Section: Discussionmentioning

confidence: 99%

Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis

Teixeira,

Wang,

Iaria

et al. 2023

Sig Transduct Target Ther

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Metastasis is the leading cause of cancer-related deaths. Transforming growth factor beta (TGF-β) signaling drives metastasis and is strongly enhanced during cancer progression. Yet, the use of on-target TGF-β signaling inhibitors in the treatment of cancer patients remains unsuccessful, highlighting a gap in the understanding of TGF-β biology that limits the establishment of efficient anti-metastatic therapies. Here, we show that TGF-β signaling hyperactivation in breast cancer cells is required for metastasis and relies on increased small extracellular vesicle (sEV) secretion. Demonstrating sEV’s unique role, TGF-β signaling levels induced by sEVs exceed the activity of matching concentrations of soluble ligand TGF-β. Further, genetic disruption of sEV secretion in highly-metastatic breast cancer cells impairs cancer cell aggressiveness by reducing TGF-β signaling to nearly-normal levels. Otherwise, TGF-β signaling activity in non-invasive breast cancer cells is inherently low, but can be amplified by sEVs, enabling invasion and metastasis of poorly-metastatic breast cancer cells. Underscoring the translational potential of inhibiting sEV trafficking in advanced breast cancers, treatment with dimethyl amiloride (DMA) decreases sEV secretion, TGF-β signaling activity, and breast cancer progression in vivo. Targeting both the sEV trafficking and TGF-β signaling by combining DMA and SB431542 at suboptimal doses potentiated this effect, normalizing the TGF-β signaling in primary tumors to potently reduce circulating tumor cells, metastasis, and tumor self-seeding. Collectively, this study establishes sEVs as critical elements in TGF-β biology, demonstrating the feasibility of inhibiting sEV trafficking as a new therapeutic approach to impair metastasis by normalizing TGF-β signaling levels in breast cancer cells.

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“…Accumulating evidence demonstrates that age-related chronic inflammation plays important roles in the progression of cancers ( Coussens and Werb, 2002 ; Ostan et al, 2015 ). Interestingly, Ror1/Ror2 are expressed highly in various types of cancers ( Zheng et al, 2016 ; Bayerlová et al, 2017 ; Hossein et al, 2017 ; Hasan et al, 2018 ; Astudillo, 2021 ). Enhanced expression of Ror1 and/or Ror2 in cancer cells can promote their proliferation, migration, invasion, survival or chemoresistance through activation of Rho-family GTPases, c-Src, MAP kinases or Akt in Wnt5a-dependent and/or -independent manners ( Enomoto et al, 2009 ; Zhang et al, 2012 ; Ida et al, 2016 ; Nishita et al, 2017 ; Hasan et al, 2019 ).…”

Section: The Ror-family Receptors In Age-related Diseasesmentioning

confidence: 99%

The Ror-Family Receptors in Development, Tissue Regeneration and Age-Related Disease

Endo

Kamizaki

Minami

2022

Front. Cell Dev. Biol.

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The Ror-family proteins, Ror1 and Ror2, act as receptors or co-receptors for Wnt5a and its related Wnt proteins to activate non-canonical Wnt signaling. Ror1 and/or Ror2-mediated signaling plays essential roles in regulating cell polarity, migration, proliferation and differentiation during developmental morphogenesis, tissue-/organo-genesis and regeneration of adult tissues following injury. Ror1 and Ror2 are expressed abundantly in developing tissues in an overlapping, yet distinct manner, and their expression in adult tissues is restricted to specific cell types such as tissue stem/progenitor cells. Expression levels of Ror1 and/or Ror2 in the adult tissues are increased following injury, thereby promoting regeneration or repair of these injured tissues. On the other hand, disruption of Wnt5a-Ror2 signaling is implicated in senescence of tissue stem/progenitor cells that is related to the impaired regeneration capacity of aged tissues. In fact, Ror1 and Ror2 are implicated in age-related diseases, including tissue fibrosis, atherosclerosis (or arteriosclerosis), neurodegenerative diseases, and cancers. In these diseases, enhanced and/or sustained (chronic) expression of Ror1 and/or Ror2 is observed, and they might contribute to the progression of these diseases through Wnt5a-dependent and -independent manners. In this article, we overview recent advances in our understanding of the roles of Ror1 and Ror2-mediated signaling in the development, tissue regeneration and age-related diseases, and discuss their potential to be therapeutic targets for chronic inflammatory diseases and cancers.

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A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer

Cited by 6 publications

References 78 publications

Cancer-associated fibroblast-derived ROR2 induces WNT/PCP activation and polarized migration in receiving gastric cancer cells

Cancer-associated fibroblast-derived ROR2 induces WNT/PCP activation and polarized migration in receiving gastric cancer cells

Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis

The Ror-Family Receptors in Development, Tissue Regeneration and Age-Related Disease

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