<scp>YAP</scp>/<scp>BRD4</scp>‐controlled <scp>ROR1</scp> promotes tumor‐initiating cells and hyperproliferation in pancreatic cancer

Yamazaki, Masaya; Hino, Shinjiro; Usuki, Shingo; Miyazaki, Yoshihiro; Oda, Tatsuya; Nakao, Mitsuyoshi; Ito, Takaaki; Yamagata, Kazuya

doi:10.15252/embj.2022112614

Cited by 19 publications

(21 citation statements)

References 88 publications

(95 reference statements)

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“…The molecular characterization of various cancers has revealed a considerable degree of intratumoral heterogeneity with distinct cancer cell populations that exhibit genomic and phenotypic diversity [40]. Recent studies have revealed that this applies also to ROR1 and ROR2 as both have been observed to be heterogeneously expressed in pancreatic and mammary tumors in vivo [41][42][43]. Of note, ROR1-high tumor cells were enriched after chemotherapy and displayed a partial EMT-like phenotype with a higher capacity for tumor growth, metastasis formation and therapy resistance compared to ROR1-low tumor cells [41].…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle-associated tyrosine kinase-like orphan receptors ROR1 and ROR2 promote breast cancer progression

Irmer,

Efing,

Reitnauer

et al. 2023

Cell Commun Signal

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Background Extracellular vesicles (EVs) harbor a plethora of different biomolecules, which they can transport across cells. In cancer, tumor-derived EVs thereby support the creation of a favorable tumor microenvironment. So far, EV uptake and cargo delivery into target cells have been regarded as the main mechanisms for the pro-tumoral function of EVs. To test this hypothesis, we investigated the fate of the oncogenic transmembrane Wnt tyrosine kinase-like orphan receptor 1 and 2 (ROR1, ROR2) delivered via distinct EV subpopulations to breast cancer cells and aimed to unravel their impact on tumor progression. Methods EVs were isolated by differential ultracentrifugation from cell culture supernatant as well as plasma samples from healthy individuals (n = 27) and breast cancer patients (n = 41). EVs were thoroughly characterized by electron microscopy, nanoparticle tracking analysis, immunoblot, and flow cytometry. ROR transfer to target cells was observed using microscopy-based assays and biodistribution experiments were conducted in syngeneic mice. EV impact on cancer cell migration and invasion was tested in functional assays. Results We observed that the supernatant of ROR-overexpressing cells was sufficient for transferring the receptors to ROR-negative cells. Analyzing the secretome of the ROR-overexpressing cells, we detected a high enrichment of ROR1/2 on large and small EVs, but not on large oncosomes. Interestingly, the majority of ROR-positive EVs remained attached to the target cell surface after 24 h of stimulation and was quickly removed by treatment with trypsin. Nonetheless, ROR-positive EVs increased migration and invasion of breast cancer cells, even after chemically inhibiting EV uptake, in dependence of RhoA downstream signaling. In vivo, ROR-depleted EVs tended to distribute less into organs prone for the formation of breast cancer metastases. ROR-positive EVs were also significantly elevated in the plasma of breast cancer patients and allowed to separate them from healthy controls. Conclusions The oncogenic Wnt receptors ROR1/2 are transferred via EVs to the surface of ROR-negative cancer cells, in which they induce an aggressive phenotype supporting tumor progression.

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Section: Discussionmentioning

confidence: 99%

Extracellular vesicle-associated tyrosine kinase-like orphan receptors ROR1 and ROR2 promote breast cancer progression

Irmer,

Efing,

Reitnauer

et al. 2023

Cell Commun Signal

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“…RNA‐sequence analyses of high ROR2‐expressing cells revealed the enrichment of molecules, such as E2F transcription factor 2 (E2F) targets and AURORA KINASES. ROR1, another ROR family molecule, is also heterogeneously expressed in pancreatic cancer tissues, and plays roles in cell proliferation and tumor initiation with AURORA KINASE and the activation of E2F 46 …”

Section: Significance Of Ascl1 In Sclcmentioning

confidence: 99%

Molecular pathology of small cell lung cancer: Overview from studies on neuroendocrine differentiation regulated by ASCL1 and Notch signaling

Ito

2024

Pathology International

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Pulmonary neuroendocrine (NE) cells are rare airway epithelial cells. The balance between Achaete‐scute complex homolog 1 (ASCL1) and hairy and enhancer of split 1, one of the target molecules of the Notch signaling pathway, is crucial for NE differentiation. Small cell lung cancer (SCLC) is a highly aggressive lung tumor, characterized by rapid cell proliferation, a high metastatic potential, and the acquisition of resistance to treatment. The subtypes of SCLC are defined by the expression status of NE cell‐lineage transcription factors, such as ASCL1, which roles are supported by SRY‐box 2, insulinoma‐associated protein 1, NK2 homeobox 1, and wingless‐related integration site signaling. This network reinforces NE differentiation and may induce the characteristic morphology and chemosensitivity of SCLC. Notch signaling mediates cell‐fate decisions, resulting in an NE to non‐NE fate switch. The suppression of NE differentiation may change the histological type of SCLC to a non‐SCLC morphology. In SCLC with NE differentiation, Notch signaling is typically inactive and genetically or epigenetically regulated. However, Notch signaling may be activated after chemotherapy, and, in concert with Yes‐associated protein signaling and RE1‐silencing transcription factor, suppresses NE differentiation, producing intratumor heterogeneity and chemoresistance. Accumulated information on the molecular mechanisms of SCLC will contribute to further advances in the control of this recalcitrant cancer.

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“…Clinical studies further indicated that in pancreatic cancer patients, BRD4 (high)/caveolin-2 (high) was associated with shorter disease-free survival. Another study by Yamazaki et al 529 further reported that YAP/BRD4 binding at the enhancer region is associated with transcriptional activation of receptor tyrosine kinase-like orphan receptor 1 (ROR1), thereby promoting tumor growth and metastasis.…”

Section: Diseases Associated With Mutation Of Transcription Co-activa...mentioning

confidence: 99%

Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases

Talukdar,

Chatterji

2023

Sig Transduct Target Ther

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Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and the co-activators. Deregulation of these regulatory molecules is associated with cell state transitions, which in turn is accountable for diverse maladies, including developmental disorders, metabolic disorders, and most significantly, cancer. A decade back most transcription factors, the key enablers of disease development, were historically viewed as ‘undruggable’; however, in the intervening years, a wealth of literature validated that they can be targeted indirectly through transcriptional co-activators, their confederates in various physiological and molecular processes. These co-activators, along with transcription factors, have the ability to initiate and modulate transcription of diverse genes necessary for normal physiological functions, whereby, deregulation of such interactions may foster tissue-specific disease phenotype. Hence, it is essential to analyze how these co-activators modulate specific multilateral processes in coordination with other factors. The proposed review attempts to elaborate an in-depth account of the transcription co-activators, their involvement in transcription regulation, and context-specific contributions to pathophysiological conditions. This review also addresses an issue that has not been dealt with in a comprehensive manner and hopes to direct attention towards future research that will encompass patient-friendly therapeutic strategies, where drugs targeting co-activators will have enhanced benefits and reduced side effects. Additional insights into currently available therapeutic interventions and the associated constraints will eventually reveal multitudes of advanced therapeutic targets aiming for disease amelioration and good patient prognosis.

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YAP/BRD4‐controlled ROR1 promotes tumor‐initiating cells and hyperproliferation in pancreatic cancer

Cited by 19 publications

References 88 publications

Extracellular vesicle-associated tyrosine kinase-like orphan receptors ROR1 and ROR2 promote breast cancer progression

Extracellular vesicle-associated tyrosine kinase-like orphan receptors ROR1 and ROR2 promote breast cancer progression

Molecular pathology of small cell lung cancer: Overview from studies on neuroendocrine differentiation regulated by ASCL1 and Notch signaling

Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases

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