WLS-Wnt signaling promotes neuroendocrine prostate cancer

Bland, Tyler; Wang, Jing; Liu, Yin; Pu, Tianjie; Li, Jingjing; Gao, Jin; Lin, Tzu Ping; Gao, Allen C.; Wu, Bainan

doi:10.1016/j.isci.2020.101970

Cited by 39 publications

(43 citation statements)

References 64 publications

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“…One possible explanation is that the high level of WLS expression in advanced CRPC tumors is indicative of Wnt ligand secretion driving noncanonical rather than canonical Wnt signaling. This is supported by a recent study that implicates WLS in the activation of noncanonical ROR2/PKCδ/ERK signaling to promote the castration‐resistant NEPC phenotype 72 . Significantly, this study as well as other work presented at the meeting found that prostate tumors with high WLS expression are highly sensitive to inhibitors of porcupine (PORCN) (i.e., LGK974, ETC159) (Balk et al, unpublished), an O'acyltransferase which is required for Wnt ligand secretion.…”

Section: Wnt Signaling and The Challenges Of Targeted Therapysupporting

confidence: 60%

Prostate cancer research in the 21st century; report from the 2021 Coffey‐Holden prostate cancer academy meeting

et al. 2021

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Introduction The 2021 Coffey‐Holden Prostate Cancer Academy (CHPCA) Meeting, “Prostate Cancer Research in the 21st Century,” was held virtually, from June 24–25, 2021. Methods The CHPCA Meeting is organized by the Prostate Cancer Foundation as a unique discussion‐oriented meeting focusing on critical topics in prostate cancer research envisioned to bridge the next major advances in prostate cancer biology and treatment. The 2021 CHPCA Meeting was virtually attended by 89 investigators and included 31 talks over nine sessions. Results Major topic areas discussed at the meeting included: cancer genomics and sequencing, functional genomic approaches to studying mediators of plasticity, emerging signaling pathways in metastatic castration resistant prostate cancer, Wnt signaling biology and the challenges of targeted therapy, clonal hematopoiesis, neuroendocrine cell plasticity and antitumor immunity, cancer immunotherapy and its synergizers, and imaging the tumor microenvironment and metabolism. Discussion This meeting report summarizes the research presented at the 2021 CHPCA Meeting. We hope that publication of this knowledge will accelerate new understandings and the development of new biomarkers and treatments for prostate cancer.

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Section: Wnt Signaling and The Challenges Of Targeted Therapysupporting

confidence: 60%

Prostate cancer research in the 21st century; report from the 2021 Coffey‐Holden prostate cancer academy meeting

et al. 2021

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“…Notably, the relationship between ROR2 and the MAPK/ERK pathway had not been explored in depth to this date. Only a recent article, described that ROR2 is required for Wntless-dependent activation of ERK in neuroendocrine prostate cancer [34]. Despite melanoma cells present high constitutive activity of ERK, overexpression of ROR2 increased p-ERK levels even further.…”

Section: Discussionmentioning

confidence: 99%

ROR2 Promotes EMT and Necrosis by Hyperactivating ERK in Melanoma

Castro

Barbero

Villanueva

et al. 2021

Preprint

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PurposeReceptor tyrosine kinase-like orphan receptor 2 (ROR2) has been shown to play opposite roles in the progression of different tumor types. In melanoma, ROR2 was shown to associate with a more invasive phenotype and to contribute to experimental lung colonization. However, the underlying mechanisms regulated by ROR2 have not been elucidated. More importantly, it has not been established whether ROR2 is just a marker or a driver of melanoma aggressiveness. MethodsGain and loss-of-function experiments were applied to study the biological function of ROR2 in melanoma. Transwell assays and Western blots were used to evaluate cell migration and both expression and activation of Epithelial-Mesenchymal Transition (EMT) markers and signaling proteins. The role of ROR2 in vivo was assessed in xenotransplantation experiments.ResultsWe describe that ROR2 promotes EMT by inducing cadherin switch and the upregulation of the transcription factors ZEB1, Twist, Slug, Snail, and HIF1A, together with a mesenchymal phenotype and increased migration. ROR2 association with EMT is also observed in melanoma samples. ROR2 exerts these effects by hyperactivating the MAPK/ERK pathway far above the typical high constitutive activity observed in melanoma. ROR2 also promoted EMT, invasion, and necrosis in xenotransplanted mice. This important role of ROR2 translates into melanoma patient’s prognosis since patients with lymph node metastasis displaying elevated ROR2 levels have reduced overall survival and distant metastasis-free survival.Conclusions These results demonstrate that ROR2 contributes to melanoma progression by hyperactivating ERK and inducing EMT and necrosis. Thus, ROR2 can be an attractive therapeutic target for metastatic melanoma.

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“…On the other hand, PCa cells with no AR expression may also be accumulated [98,99], and thus, the tumor progression is no longer dependent on AR signaling, such as the neuroendocrine prostate tumor [100]. Those cells may rely more on other nuclear hormone receptor signaling [101][102][103], or they may activate other AR independent signaling cascades [18,104,105] (Figure 2; right panel). In such cases, BAT also may not be effective anymore.…”

Section: Pi3k-akt-mtor In Pca Progression and Ar-targeted Therapy Resistancementioning

confidence: 99%

Role of PI3K-AKT-mTOR Pathway as a Pro-Survival Signaling and Resistance-Mediating Mechanism to Therapy of Prostate Cancer

Pungsrinont

Kallenbach

Baniahmad

2021

IJMS

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Androgen deprivation therapy (ADT) and androgen receptor (AR)-targeted therapy are the gold standard options for treating prostate cancer (PCa). These are initially effective, as localized and the early stage of metastatic disease are androgen- and castration-sensitive. The tumor strongly relies on systemic/circulating androgens for activating AR signaling to stimulate growth and progression. However, after a certain point, the tumor will eventually develop a resistant stage, where ADT and AR antagonists are no longer effective. Mechanistically, it seems that the tumor becomes more aggressive through adaptive responses, relies more on alternative activated pathways, and is less dependent on AR signaling. This includes hyperactivation of PI3K-AKT-mTOR pathway, which is a central signal that regulates cell pro-survival/anti-apoptotic pathways, thus, compensating the blockade of AR signaling. The PI3K-AKT-mTOR pathway is well-documented for its crosstalk between genomic and non-genomic AR signaling, as well as other signaling cascades. Such a reciprocal feedback loop makes it more complicated to target individual factor/signaling for treating PCa. Here, we highlight the role of PI3K-AKT-mTOR signaling as a resistance mechanism for PCa therapy and illustrate the transition of prostate tumor from AR signaling-dependent to PI3K-AKT-mTOR pathway-dependent. Moreover, therapeutic strategies with inhibitors targeting the PI3K-AKT-mTOR signal used in clinic and ongoing clinical trials are discussed.

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WLS-Wnt signaling promotes neuroendocrine prostate cancer

Cited by 39 publications

References 64 publications

Prostate cancer research in the 21st century; report from the 2021 Coffey‐Holden prostate cancer academy meeting

Prostate cancer research in the 21st century; report from the 2021 Coffey‐Holden prostate cancer academy meeting

ROR2 Promotes EMT and Necrosis by Hyperactivating ERK in Melanoma

Role of PI3K-AKT-mTOR Pathway as a Pro-Survival Signaling and Resistance-Mediating Mechanism to Therapy of Prostate Cancer

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