Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

Chai, Annie Wai Yeeng; Yee, Pei San; Price, Stacey; Yee, Shi Mun; Lee, Hui Mei; Tiong, Vivian Kh; Gonçalvès, Emanuel; Behan, Fiona M.; Bateson, Jess; Gilbert, James; Tan, Aik Choon; McDermott, Ultan; Garnett, Mathew J.; Cheong, Sok Ching

doi:10.7554/elife.57761

Cited by 39 publications

(45 citation statements)

References 95 publications

(175 reference statements)

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“…Furthermore, it has to be analyzed whether there are differences in regard to Trop-2 expression between Asian and Caucasian OSCC. Several studies on the genomic landscape of Asian and Caucasian OSCC have already revealed distinct molecular differences, which are supposed to be partly due to varying population-specific risk factors (summarized in [ 35 ]).…”

Section: Discussionmentioning

confidence: 99%

Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

Erber

Spoerl

Mamilos

et al. 2021

IJMS

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Oral cancer often presents with aggressive behavior and a high risk of recurrence and metastasis. For oral squamous cell carcinoma (OSCC), which is the most frequent histological subtype, therapy strategies include surgery, radiation therapy, chemotherapy, immune checkpoint inhibitors, and EGFR inhibitors. Recently, a Trop-2 antibody-drug conjugate (ADC) has been approved in the United States of America for the treatment of advanced triple-negative breast cancer. However, this ADC has also been tested in other solid tumors including head & neck squamous cell carcinoma. The prognostic impact of Trop-2 has already been reported for several cancers. We studied the prognostic influence of Trop-2 protein expression on OSCC patients’ survival. The cohort comprised n = 229 OSCC patients with available archived tumor tissue and corresponding non-neoplastic oral mucosa tissue. Using immunohistochemistry, we investigated Trop-2 expression in both the central and peripheral regions of each tumor and in corresponding non-neoplastic oral mucosa. In patients suffering from OSCC with combined high central and low peripheral Trop-2 expression, five-year overall survival (OS) was 41.2%, whereas 55.6% of OSCC patients who presented lower central and/or higher peripheral tumoral Trop-2 expression were alive after five years (p = 0.075). In multivariate Cox regression, the expression pattern of high central tumoral and lower peripheral Trop-2 expression was significantly correlated with impaired OS (HR = 1.802, 95%-CI: 1.134–2.864; p = 0.013) and recurrence-free survival (RFS) (HR = 1.633, 95%-CI: 1.042–2.560; p = 0.033), respectively, when adjusting for co-variables. Hence, Trop-2 may serve as an independent prognostic biomarker in OSCC. In subsequent studies, the pathophysiological meaning of downregulated Trop-2 expression in the OSCC periphery has to be analyzed.

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Section: Discussionmentioning

confidence: 99%

Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

Erber

Spoerl

Mamilos

et al. 2021

IJMS

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“…In many types of cancers including HNSCC, the hippo pathway is abnormally inactivated; thus, YAP/TAZ is highly expressed. 31,32 Previous studies have revealed that aberrant Hippo signaling promotes tumor progression including EMT, chemotherapy resistance, and CSCs generation. 33,34 Inhibition of YAP/TAZ using verteporfin (VP) has been recently shown to suppress proliferation and attenuate EMT and stemness in HNSCC CSCs.…”

Section: Introductionmentioning

confidence: 99%

Melatonin and verteporfin synergistically suppress the growth and stemness of head and neck squamous cell carcinoma through the regulation of mitochondrial dynamics

Shin

Seo

et al. 2021

Journal of Pineal Research

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“…The fitness cost of gene knockout can be assessed from programmed gene editing, an approach that is employed for the unbiased identification of essential genes in other organisms and disease settings (Chai et al, 2020; Kim and Hart, 2021). Our present findings confirmed the power of RNA-guided targeted mutation to define essentiality and relevance of parasite proteins in infection-associated morbidity and malignancy.…”

Section: Discussionmentioning

confidence: 99%

Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini

Chaiyadet

Tangkawattana

Smout

et al. 2021

Preprint

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Infection with the food-borne liver fluke Opisthorchis viverrini is the principal risk factor for cholangiocarcinoma (CCA; bile duct cancer) in the Lower Mekong River Basin countries including Thailand, Lao PDR, Vietnam, Myanmar and Cambodia. Using gene edited liver flukes in a hamster model of CCA involving concurrent infection and administration of sub-carcinogenic levels of nitrosamine, we explored the role of the fluke granulin-like growth factor Ov-GRN-1 in malignancy. We produced programmed gene knockout flukes (ΔOv-grn-1) by delivery of a CRISPR/Cas9/gRNA system by square wave electroporation. Targeted genome sequencing confirmed Cas9-catalyzed mutations in target parasite genes, and the rapid depletion of transcripts and the targeted proteins. Hamsters were infected with gene edited larval parasites and exposed to sub-carcinogenic levels of dimethyl nitrosamine in drinking water. Whereas Ov-grn-1 gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes, less hepatobiliary tract disease manifested during chronic infection with ΔOv-grn-1 worms in comparison to hamsters infected with control parasites. Specifically, immunohistochemical analysis of thin sections of hamster livers revealed markedly less fibrosis surrounding flukes and less global liver fibrosis as a result of infection with ΔOv-grn-1 worms, minimal biliary epithelial cell proliferation, and markedly fewer mutations of TP53 in biliary epithelial cells. Moreover, fewer hamsters developed high grade CCA when infected with ΔOv-grn-1 flukes compared to controls. The clinically-relevant pathophysiological phenotype of the livers of the hamsters confirmed a role for this parasite secreted growth factor in morbidity and malignancy during opisthorchiasis.

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Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

Cited by 39 publications

References 95 publications

Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

Melatonin and verteporfin synergistically suppress the growth and stemness of head and neck squamous cell carcinoma through the regulation of mitochondrial dynamics

Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini

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