The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer

Zhu, Qionghua; Fang, Liang; Heuberger, Julian; Kranz, Andrea; Schipper, Jörg; Scheckenbach, Kathrin; Vidal, Ramón; Sunaga-Franze, Daniele Yumi; Müller, Marion; Wulf-Goldenberg, Annika; Sauer, Sascha; Birchmeier, Walter

doi:10.1016/j.celrep.2018.12.059

Cited by 22 publications

(21 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5a, Supplementary Fig 11a). In agreement with our model, in which tumors are induced by activation of β-catenin and Bmpr1a mutations via the basalspecific K14-cre promoter 16,17 , we find that this trajectory initiates in basal tumor cells, further proceeds through the two CSClike subpopulations, and ends in the luminal Clu+ cell cluster with continuous transitions in between (Fig. 5a, b).…”

Section: Resultssupporting

confidence: 91%

“…In line with our transcriptome data, Clu and Wfdc18 distinctively stained K8positive luminal-like cells within the tumor region. Nuclear βcatenin is considered to be the hallmark of active Wnt signaling which ultimately drives the expression of its target genes 35,36 and was previously described to be a key feature of CSCs in several cancers including our model 16,17,37 . We, therefore, used this as an additional marker, and found that nuclear β-catenin-positive cells were generally K8 negative and greatly overlapped with high Axin2, but only partially with Ptn and Wif1 stainings.…”

Section: Resultsmentioning

confidence: 97%

“…With the aim to better understand these Wnt-specific mechanisms, we thus created a mouse model 16 with K14-credriven β-catenin gain-of-function (β-cat GOF ) and Bmpr1a loss-offunction (Bmpr1a LOF ) mutations. We showed that these mice developed very specific salivary gland SCCs within 100 days after birth which contained highly self-renewing Wnt-dependent CD24 + CD29 + CSCs which, upon isolation and injection into NOD/SCID mice, produced fast-growing tumors 16,17 . These CSCs showed high activity of the stem cell-associated SSEA1 marker as well as nuclear β-catenin and Wnt-specific target genes such as Axin2 which were not found in other subpopulations within the tumor 16 .…”

mentioning

confidence: 97%

“…To gain a more basic understanding of tumorigenesis, we here used single-cell transcriptomics together with our Wnt-dependent double-mutant salivary gland SCC mouse model 16,17 to systematically study CSCs in a controlled setting in vivo. Our setup ( Fig.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Tracing tumorigenesis in a solid tumor model at single-cell resolution

et al. 2020

Self Cite

View full text Add to dashboard Cite

Characterizing the complex composition of solid tumors is fundamental for understanding tumor initiation, progression and metastasis. While patient-derived samples provide valuable insight, they are heterogeneous on multiple molecular levels, and often originate from advanced tumor stages. Here, we use single-cell transcriptome and epitope profiling together with pathway and lineage analyses to study tumorigenesis from a developmental perspective in a mouse model of salivary gland squamous cell carcinoma. We provide a comprehensive cell atlas and characterize tumor-specific cells. We find that these cells are connected along a reproducible developmental trajectory: initiated in basal cells exhibiting an epithelial-tomesenchymal transition signature, tumorigenesis proceeds through Wnt-differential cancer stem cell-like subpopulations before differentiating into luminal-like cells. Our work provides unbiased insights into tumor-specific cellular identities in a whole tissue environment, and emphasizes the power of using defined genetic model systems.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 97%

mentioning

confidence: 97%

mentioning

confidence: 99%

See 2 more Smart Citations

Tracing tumorigenesis in a solid tumor model at single-cell resolution

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Together, these proteins were shown to interact in promoting self-renewal in HNSCC tumor propagating cells, which were highly proliferative and highly tumorigenic. The formation of this complex could be blocked by ICG-001 [130] or LF3, an inhibitor of interaction between β-catenin and TCF4 [132], which resulted in the loss of the capacity of tumor propagating cells for self-renewal and reduced tumor formation in vivo.…”

Section: Functional Significance Of Wnt/β-catenin Pathway Dysregulationmentioning

confidence: 99%

The Significance of the Dysregulation of Canonical Wnt Signaling in Head and Neck Squamous Cell Carcinomas

Paluszczak

2020

Cells

View full text Add to dashboard Cite

The knowledge about the molecular alterations which are found in head and neck squamous cell carcinomas (HNSCC) has much increased in recent years. However, we are still awaiting the translation of this knowledge to new diagnostic and therapeutic options. Among the many molecular changes that are detected in head and neck cancer, the abnormalities in several signaling pathways, which regulate cell proliferation, cell death and stemness, seem to be especially promising with regard to the development of targeted therapies. Canonical Wnt signaling is a pathway engaged in the formation of head and neck tissues, however it is not active in adult somatic mucosal cells. The aim of this review paper is to bring together significant data related to the current knowledge on the mechanisms and functional significance of the dysregulation of the Wnt/β-catenin pathway in head and neck tumors. Research evidence related to the role of Wnt signaling activation in the stimulation of cell proliferation, migration and inhibition of apoptosis in HNSCC is presented. Moreover, its role in promoting stemness traits in head and neck cancer stem-like cells is described. Evidence corroborating the hypothesis that the Wnt signaling pathway is a very promising target of novel therapeutic interventions in HNSCC is also discussed.Cells 2020, 9, 723 2 of 20 blocking the interaction between PD-1 receptor and PD-L1, may be beneficial in patients with advanced, metastatic or recurrent HNSCC [7]. However, other therapeutic options are also necessary for the better clinical management of HNSCC patients. To that end, molecular alterations observed in HNSCC need to be studied in detail, in order to point to promising drug targets. Mechanisms of Wnt/β-Catenin Pathway Activation in HNSCCRecent genomic analyses have shown the prevalence of genetic driver alterations in HNSCC, which most frequently affect genes associated with receptor tyrosine kinase (e.g., EGFR, MET, KIT), PI3K, p53, Notch or Hippo signaling pathways. On the other hand, genetic alterations in genes related to canonical Wnt signaling were rarely detected in HNSCC [8,9]. In contrast to colorectal cancers, which show molecular alterations driving Wnt signaling activation in around 90% of cases [9], HNSCC were shown to lack CTNNB1 mutations and APC mutations were present infrequently [10][11][12][13][14][15][16]. The mutations of FAT1 tumor suppressor, which encodes a protocadherin protein that binds and inactivates β-catenin, were detected in some cases of HNSCC [17]. However, the activation of the Wnt/β-catenin pathway in HNSCC seems to be more prevalent than it is suggested by genetic findings, due to cross-talk with other molecular alterations, which can lead to pathway cross-activation. Indeed, it has been shown that β-catenin can be activated via enhanced EGFR or PI3K signaling, which belong to the most frequently dysregulated signaling pathways in HNSCC. In this regard, elevated EGFR expression was associated with delocalized β-catenin expression [13]. In another study, the nuclear ...

show abstract

Pathogenic and Therapeutic Role of H3K4 Family of Methylases and Demethylases in Cancers

et al. 2019

View full text Add to dashboard Cite

Histone modifications occupy an essential position in the epigenetic landscape of the cell, and their alterations have been linked to cancers. Histone 3 lysine 4 (H3K4) methylation has emerged as a critical epigenetic cue for the regulation of gene transcription through dynamic modulation by several H3K4 methyltransferases (writers) and demethylases (erasers). Any disturbance in the delicate balance of writers and erasers can result in the mis-regulation of H3K4 methylation, which has been demonstrated in several human cancers. Therefore, H3K4 methylation has been recognized as a putative therapeutic or prognostic tool and drug trials of different inhibitors of this process have demonstrated promising results. Henceforth, more detailed knowledge of H3K4 methylation is utmost important for elucidating the complex cellular processes, which might help in improving the disease outcome. The primary focus of this review will be directed on deciphering the role of H3K4 methylation along with its writers/erasers in different cancers.

show abstract

The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer

Cited by 22 publications

References 78 publications

Tracing tumorigenesis in a solid tumor model at single-cell resolution

Tracing tumorigenesis in a solid tumor model at single-cell resolution

The Significance of the Dysregulation of Canonical Wnt Signaling in Head and Neck Squamous Cell Carcinomas

Pathogenic and Therapeutic Role of H3K4 Family of Methylases and Demethylases in Cancers

Contact Info

Product

Resources

About