Decreased <scp>FOXJ1</scp> expression and its ciliogenesis programme in aggressive ependymoma and choroid plexus tumours

Abedalthagafi, Malak; Wu, Michael P; Merrill, Parker; Du, Ziwei; Woo, Terri; Sheu, Shu-Hsien; Hurwitz, Shelley; Ligon, Keith L.; Santagata, Sandro

doi:10.1002/path.4682

Cited by 33 publications

(31 citation statements)

References 73 publications

(169 reference statements)

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“…We recently reported that FOXJ1 is expressed in the nucleus of ciliated ependymal cells that line the ventricle of the human brain, as well as in well-differentiated ependymoma and choroid plexus tumors (39, 41). Using an immunohistochemistry protocol developed for that study, we analyzed the expression of FOXJ1 protein in a panel of sixteen Rathke’s cleft cysts (Supplemental Table 1; Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…Such markers may not only improve diagnostic accuracy, but may also provide useful insights into the biology of lesions, which may suggest novel therapeutic interventions. Characterization of the motile ciliogenesis program in ependymoma via FOXJ1 immunohistochemistry has already yielded interesting insights into disease biology (39). We expect that FOXJ1 and TUBA4A/ARL13B immunohistochemistry will prove useful in the evaluation of other tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Staining was performed as previously reported (39). In brief, tissue sections were cut at 4μm and deparaffinized in xylene and absolute alcohol.…”

Section: Methodsmentioning

confidence: 99%

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Distinct patterns of primary and motile cilia in Rathke's cleft cysts and craniopharyngioma subtypes

Coy

Sheu

et al. 2016

Modern Pathology

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Cilia are highly conserved organelles which serve critical roles in development and physiology. Motile cilia are expressed in a limited range of tissues, where they principally regulate local extracellular fluid dynamics. In contrast, primary cilia are expressed by many vertebrate cell types during interphase, and are intimately involved in the cell cycle and signal transduction. Notably, primary cilia are essential for vertebrate hedgehog pathway activity. Improved detection of motile cilia may assist in the diagnosis of some pathologic entities such as Rathke’s cleft cysts while characterizing primary cilia in neoplastic tissues may implicate cilia-dependent signaling pathways as critical for tumorigenesis. We show that immunohistochemistry for the nuclear transcription factor FOXJ1, a master regulator of motile ciliogenesis, robustly labels the motile ciliated epithelium of Rathke’s cleft cysts. FOXJ1 expression discriminates Rathke’s cleft cysts from entities in the sellar/suprasellar region with overlapping histologic features such as craniopharyngiomas. Co-immunohistochemistry for FOXJ1 and markers that highlight motile cilia such as acetylated tubulin (TUBA4A) and the small GTPase ARL13B further enhance the ability to identify diagnostic epithelial cells. In addition to highlighting motile cilia, ARL13B immunohistochemistry also robustly highlights primary cilia in formalin-fixed paraffin-embedded sections. Primary cilia are present throughout the neoplastic epithelium of adamantinomatous craniopharyngioma, but are limited to basally oriented cells near the fibrovascular stroma in papillary craniopharyngioma. Consistent with this differing pattern of primary ciliation, adamantinomatous craniopharyngiomas express significantly higher levels of SHH, and downstream targets such as PTCH1 and GLI2, compared to papillary craniopharyngiomas. In conclusion, motile ciliated epithelium can be readily identified using immunohistochemistry for FOXJ1, TUBA4A and ARL13B, facilitating the diagnosis of Rathke’s cleft cyst. Primary cilia can be identified by ARL13B immunohistochemistry in routine pathology specimens. The widespread presence of primary cilia in adamantinomatous craniopharyngioma implicates cilia-dependent hedgehog signaling in the pathogenesis of adamantinomatous craniopharyngioma.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Distinct patterns of primary and motile cilia in Rathke's cleft cysts and craniopharyngioma subtypes

Coy

Sheu

et al. 2016

Modern Pathology

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“…10). Comparing to other brain tumour types, FOXJ1 expression was increased in ependymomas, with the highest levels in PF-EPN-B tumours 16 (Extended Data Fig. 10).…”

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confidence: 89%

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Mack¹,

Pajtler

Chávez

et al. 2017

Nature

187

218

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SUMMARY Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated based on anatomical location – supratentorial region (ST) or posterior fossa (PF) – and further divided into distinct molecular subgroups that reflect differences in age of onset, gender predominance, and response to therapy1–3. The most common and aggressive subgroup, Posterior Fossa Ependymoma Group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, Posterior Fossa Ependymoma Group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses yet favourable clinical outcomes1,3. Greater than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NFκB subunit RELA (ST-EPN-RELA), and less frequently involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1).1,3,4 Subependymomas, a distinct histologic variant, can also be found within the ST and PF compartments accounting for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE, respectively1. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts with the goal of identifying essential super enhancer associated genes on which tumour cells were dependent. Enhancer regions revealed putative oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, diminished proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.

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“…A recent study published by Abedalthagafi and colleagues in the Journal of Pathology also demonstrated that assessing expression of FOXJ1 and RFX factors could serve the diagnosis and prognosis of ependymal and choroid plexus tumours [13]. The ventricles of the brain are lined by multiciliated cells and FOXJ1 as well as RFX2 expression is normally high in the ependyma and choroid plexus.…”

Section: P Walentekmentioning

confidence: 99%

Ciliary transcription factors in cancer - how understanding ciliogenesis can promote the detection and prognosis of cancer types

Walentek

2016

J. Pathol.

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Cilia play a plethora of roles in normal development and homeostasis as well as in disease. Their involvement in cell signalling processes and ability to inhibit cell cycle progression make them especially interesting subjects of investigation in the context of tumour formation and malignancy. Several key transcription factors regulate the transcriptional programme in cilia formation and some of these, eg RFX factors and FOXJ1, are implicated in cancer formation. Furthermore, RFX factors and FOXJ1 are increasingly being explored for their potential as markers to diagnose, classify and predict the outcome of cancers in patients, including recent work published in this journal on aggressive ependymoma and choroid plexus tumours. Here, some of the key findings and concepts on the roles of ciliary transcription factors in tumourigenesis are highlighted, and a brief perspective is given on how the investigation of ciliogenesis could contribute valuable tools for the diagnosis and prognosis of cancers.

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Decreased FOXJ1 expression and its ciliogenesis programme in aggressive ependymoma and choroid plexus tumours

Cited by 33 publications

References 73 publications

Distinct patterns of primary and motile cilia in Rathke's cleft cysts and craniopharyngioma subtypes

Distinct patterns of primary and motile cilia in Rathke's cleft cysts and craniopharyngioma subtypes

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Ciliary transcription factors in cancer - how understanding ciliogenesis can promote the detection and prognosis of cancer types

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