Sox2 Suppresses Gastric Tumorigenesis in Mice

Sarkar, Abby; Huebner, Aaron J.; Sulahian, Rita; Anselmo, Anthony; Xu, Xiayu; Flattery, Kyle; Desai, Niyati; Sebastián, Carlos; Yram, Mary Anna; Arnold, Katrin; Rivera, Miguel N.; Mostoslavsky, Raúl; Bronson, Roderick T.; Bass, Adam J.; Sadreyev, Ruslan I.; Shivdasani, Ramesh A.; Hochedlinger, Konrad

doi:10.1016/j.celrep.2016.07.034

Cited by 66 publications

(53 citation statements)

References 45 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SOX2 has been implicated in maintaining malignant stemness properties as an oncogene in several types of cancer 1213 , whereas it acts as a tumor suppressor by modulating Wnt-related and intestinal genes in gastric cancer 39 , indicating the context-dependent behavior of SOX2. Although chronic arsenic exposure reprograms human bronchial epithelial cells to CSCs with SOX2 expression 40 , functional role of SOX2 remains unclear in arsenic-induced CSCs.…”

Section: Discussionmentioning

confidence: 99%

Arsenic promotes the COX2/PGE2–SOX2 axis to increase the malignant stemness properties of urothelial cells

Ooki

Begum

Marchionni

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion and chemoresistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB.

show abstract

Section: Discussionmentioning

confidence: 99%

Arsenic promotes the COX2/PGE2–SOX2 axis to increase the malignant stemness properties of urothelial cells

Ooki

Begum

Marchionni

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…In support, GC cell lines reveal mutations at codon 1450 of APC that encodes a truncated form of APC that fails to negatively regulate β‐catenin, which causes constitutive activation of Wnt signalling (Sasaki et al , ). Importantly, several reports have demonstrated that conditional deletion or loss‐of‐heterozygosity of wild type Apc is sufficient to drive gastric hyperplasia and subsequent adenoma formation (Tomita et al , ; Radulescu et al ; Powell et al , ; Sarkar et al , ). Collectively, patient genomics and preclinical mouse models highlight the relevance of APC mutations in driving gastric tumourigenesis, which offer an attractive therapeutic target to treat GC patients.…”

Section: Genetic Lesions Of the β‐Catenin Destruction Complexmentioning

confidence: 99%

Winding back Wnt signalling: potential therapeutic targets for treating gastric cancers

Flanagan

Vincan

Phesse

2017

British J Pharmacology

View full text Add to dashboard Cite

Gastric cancer persists as a frequent and deadly disease that claims over 700 000 lives annually. Gastric cancer is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal cancers, making it therapeutically challenging. As such, and largely attributed to late‐stage diagnosis, gastric cancer patients show only partial response to standard chemo and targeted molecular therapies, highlighting an urgent need to develop new targeted therapies for this disease. Wnt signalling has a well‐documented history in the genesis of many cancers and is, therefore, an attractive therapeutic target. As such, drug discovery has focused on developing inhibitors that target multiple nodes of the Wnt signalling cascade, some of which have progressed to clinical trials. The collective efforts of patient genomic profiling has uncovered genetic lesions to multiple components of the Wnt pathway in gastric cancer patients, which strongly suggest that Wnt‐targeted therapies could offer therapeutic benefits for gastric cancer patients. These data have been supported by studies in mouse models of gastric cancer, which identify Wnt signalling as a driver of gastric tumourigenesis. Here, we review the current literature regarding Wnt signalling in gastric cancer and highlight the suitability of each class of Wnt inhibitor as a potential treatment for gastric cancer patients, in relation to the type of Wnt deregulation observed. Linked Articles This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc

show abstract

“…The combined data indicate a tumorigenic role of Sox2 in many cancers. In contrast, Sox2 appears to act as a tumor suppressor gene in gastric tumors driven by canonical Wnt signal activation, pointing to context-dependent activities of Sox2 in regulating cell proliferation and tumorigenesis 19 .…”

Section: Introductionmentioning

confidence: 99%

Sox2 is dispensable for primary melanoma and metastasis formation

et al. 2017

View full text Add to dashboard Cite

Tumor initiation and metastasis formation in many cancers have been associated with emergence of a gene expression program normally active in embryonic or organ-specific stem cells. In particular, the stem cell transcription factor Sox2 is not only expressed in a variety of tumors, but is also required for their formation. Melanoma, the most aggressive skin tumor, derives from melanocytes that during development originate from neural crest stem cells. While neural crest stem cells do not express Sox2, expression of this transcription factor has been reported in melanoma. However, the role of Sox2 in melanoma is controversial. To study the requirement of Sox2 for melanoma formation, we therefore performed CRISPR-Cas9-mediated gene inactivation in human melanoma cells. In addition, we conditionally inactivated Sox2 in a genetically engineered mouse model, in which melanoma spontaneously develops in the context of an intact stroma and immune system. Surprisingly, in both models, loss of Sox2 did neither affect melanoma initiation, nor growth, nor metastasis formation. The lack of a tumorigenic role of Sox2 in melanoma might reflect a distinct stem cell program active in neural crest stem cells and during melanoma formation.

show abstract

Sox2 Suppresses Gastric Tumorigenesis in Mice

Cited by 66 publications

References 45 publications

Arsenic promotes the COX2/PGE2–SOX2 axis to increase the malignant stemness properties of urothelial cells

Arsenic promotes the COX2/PGE2–SOX2 axis to increase the malignant stemness properties of urothelial cells

Winding back Wnt signalling: potential therapeutic targets for treating gastric cancers

Sox2 is dispensable for primary melanoma and metastasis formation

Contact Info

Product

Resources

About