Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness

Karvonen, Hanna; Arjama, Mariliina; Kaleva, Laura; Niininen, Wilhelmiina; Barker, Harlan; Koivisto-Korander, Riitta; Tapper, Johanna; Pakarinen, Päivi; Lassus, Heini; Loukovaara, Mikko; Bützow, Ralf; Kallioniemi, Olli; Murumägi, Astrid; Ungureanu, Daniela

doi:10.1038/s41419-020-03009-4

Cited by 48 publications

(40 citation statements)

References 48 publications

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“…ROR1, in turn, supported tumor colonization and metastasis formation at these sites [ 109 ]. Similar observations have been made in ovarian cancer, in which the synthetic glucocorticoid dexamethasone induced ROR1 expression, which correlated with elevated RHOA, YAP/TAZ, and BMI-1 levels in a panel of ovarian cancer cell lines as well as in the primary patient-derived cells [ 167 ]. As both YAP/TAZ and BMI-1 regulate the differentiation and self-renewing capacity of cancer stem cells, these observations could provide the molecular basis underlying the ROR1-associated stemness phenotype.…”

Section: Wnt/ror Signaling At a Glancesupporting

confidence: 74%

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

Menck

Heinrichs

Baden

et al. 2021

Cells

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The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca2+ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.

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Section: Wnt/ror Signaling At a Glancesupporting

confidence: 74%

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

Menck

Heinrichs

Baden

et al. 2021

Cells

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“…The relevance of ROR1 and its therapeutic role has been recently explored in ovarian cancer. Indeed, it has been demonstrated that ROR1 has an important therapeutic role in such a neoplastic disease because glucocorticoids anti-inflammatory agents (generally administred as adjuvant to chemotherapy) may induce chemoresistance by promoting ROR1-mediated stemness [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Functional and clinical significance of ROR1 in lung adenocarcinoma

et al. 2020

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Background Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is normally detectable in embryonic tissues and absent in adult tissues. ROR1 was shown to inhibit apoptosis, potentiate EGFR signaling and reported to be overexpressed and associated with poor prognosis in several tumor models. This study aimed to assess the expression of ROR1 in lung adenocarcinoma (AC) patients. Methods We analyzed ROR1 expression by quantitative real-time PCR (qRT-PCR) in 56 histologically confirmed lung AC, stage I to IV, in addition we evaluated its association with TTF-1 (thyroid transcription factor-1) expression and the main molecular alterations involved in lung cancerogenesis. Results ROR1 overexpression was observed in 28.6% of the entire cohort, using a cut-off of 1, or in 51.8% of the cases using the median value as threshold. Among patients without any genetic alteration, ROR1 overexpression was observed in 34.8% considering a cut-off of 1 and 52.2% considering the median value. The distribution of ROR1 was homogeneous among the different molecular categories: we found no association of ROR1 expression and the presence of gene mutations/rearrangements or the expression of TTF-1. Conclusions ROR1 overexpression could constitute a potential therapeutic target because altered in a consistent number of lung AC, especially in cases without druggable genetic alterations. ROR1 expression is independent of classical lung cancer molecular alterations and not correlated, in a Caucasian cohort, to TTF-1 expression.

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“…This indicates that in gynaecological cancer, GR expression increases risk of death or progression by 68% and 83%, respectively ( Figure 3 and Figure 4 ). Indeed, GR signalling has been shown to negatively impact ovarian cancer disease outcomes by promoting ROR-1 induced stemness and inducing taxane resistance, a mainstay of ovarian cancer treatment [ 67 ]. Moreover, addition of GR antagonists to chemotherapy regimens has improved response in patient derived xenograft PDX models of ovarian cancers and they are in development for endometrioid cancer [ 68 , 69 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of Glucocorticoid Receptor Expression in Cancer: A Systematic Review and Meta-Analysis

Bakour

Moriarty

Moore

et al. 2021

Cancers

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In solid malignancies, the glucocorticoid receptor (GR) signalling axis is associated with tumour progression and GR antagonists are in clinical development. Therefore, GR expression may be a useful potential prognostic or predictive biomarker for GR antagonist therapy in cancer. The aim of this review is to investigate if GR expression in tumours is predictive of overall survival or progression free survival. Twenty-five studies were identified through systematic searches of three databases and a meta-analysis conducted using a random effects model, quantifying statistical heterogeneity. Subgroup analysis was conducted for cancer types and publication bias was assessed via funnel plots. There was high heterogeneity in meta-analysis of the studies in all cancer types, which found no association between high GR expression with overall survival (pooled unadjusted HR 1.16, 95% CI (0.89–1.50), n = 2814; pooled adjusted HR 1.02, 95% CI (0.77–1.37), n = 2355) or progression-free survival (pooled unadjusted HR 1.12, 95% CI (0.88–1.42), n = 3365; pooled adjusted HR 1.04, 95% CI (0.6–1.81), n = 582) across all cancer types. However, subgroup meta-analyses showed that high GR expression in gynaecological cancers (endometrial and ovarian) (unadjusted HR 1.83, 95% CI (1.31–2.56), n = 664) and early stage, untreated triple negative breast cancers (TNBCs) (unadjusted HR 1.73, 95% CI (1.35–2.23), n = 687) is associated with disease progression. GR expression in late stage, chemotherapy treated TNBC was not prognostic (unadjusted HR 0.76, 95% CI (0.44, 1.32), n = 287). In conclusion, high GR expression is associated with an increased risk of disease progression in gynaecological and early stage, untreated TNBC. Additional studies are required to elucidate the tumour specific function of the GR receptor in order to ensure GR antagonists target the correct patient groups.

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Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness

Cited by 48 publications

References 48 publications

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

Functional and clinical significance of ROR1 in lung adenocarcinoma

Prognostic Significance of Glucocorticoid Receptor Expression in Cancer: A Systematic Review and Meta-Analysis

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