Characterization of a head and neck cancer-derived cell line panel confirms the distinct TP53-proficient copy number-silent subclass

Harten, Anne M. van; Poell, Jos B.; Buijze, Marijke; Brink, Arjen; Wells, Susanne I.; Leemans, C. René; Wolthuis, Rob M. F.; Brakenhoff, Ruud H.

doi:10.1016/j.oraloncology.2019.09.004

Cited by 26 publications

(33 citation statements)

References 37 publications

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“…Others reported that Yes knockdown increases proliferation and migration in fibroblasts, potentially explaining the slight increase in viability in the tested fibroblasts 36,37 . Interestingly, we compared the sensitivity to Wee1 inhibition in a TP53 wild-type HNSCC cell line and after TP53 CRISPR/Cas9 knockout, and no difference in vulnerability was observed suggesting a somewhat more complex interaction with mutated TP53 15 . The available inhibitor Adavosertib, currently used in several clinical trials in combination with other drugs, is reported to be well tolerated, with fatigue, nausea, thrombocytopenia and diarrhea as most common adverse events [20][21][22]38 .…”

Section: Discussionmentioning

confidence: 96%

“…FaDu, OVCAR3 and SKOV3 were obtained from the American Type Culture Collection. The other used cell lines were obtained and cultured as described before 5,12,13,15,[49][50][51] . All cells were cultured without antibiotics, were mycoplasma negative and checked regularly (Mycoalert, Lonza, LT07-318), and were authenticated by visual inspection and genetic profiling on indication.…”

Section: Discussionmentioning

confidence: 99%

“…collateral lethality. Low-coverage whole-genome sequencing of the cell lines was performed as described previously 5,15 . The obtained DNA copy number (CN) data and siRNA viability scores were analyzed using the gene-set model approach 14 .…”

Section: Discussionmentioning

confidence: 99%

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Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Harten

Boer

Kemp

et al. 2020

Sci Rep

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HPV-negative head and neck squamous cell carcinomas (HNSCCs) develop in precancerous changes in the mucosal lining of the upper-aerodigestive tract. these precancerous cells contain cancerassociated genomic changes and cause primary tumors and local relapses. therapeutic strategies to eradicate these precancerous cells are very limited. Using functional genomic screens, we identified the therapeutic vulnerabilities of premalignant mucosal cells, which are shared with fully malignant HNSCC cells. We screened 319 previously identified tumor-lethal siRNAs on a panel of cancer and precancerous cell lines as well as primary fibroblasts. In total we identified 147 tumor-essential genes including 34 druggable candidates. Of these 34, 13 were also essential in premalignant cells. We investigated the variable molecular basis of the vulnerabilities in tumor and premalignant cell lines and found indications of collateral lethality. Wee1-like kinase (WEE1) was amongst the most promising targets for both tumor and precancerous cells. All four precancerous cell lines were highly sensitive to Wee1 inhibition by Adavosertib (AZD1775), while primary keratinocytes tolerated this inhibitor. Wee1 inhibition caused induction of DNA damage during S-phase followed by mitotic failure in (pre)cancer cells. In conclusion, we uncovered Wee1 inhibition as a promising chemopreventive strategy for precancerous cells, with comparable responses as fully transformed HnScc cells. Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal lining of the upper-aerodigestive tract and account for around 5% of the total cancer incidence 1,2. The main risk factors for head and neck cancer are smoking and excessive alcohol consumption, infection with a high-risk type of the human papillomavirus (HPV), or genetic predisposition such as Fanconi anemia (FA) 2. FA is characterized by congenital abnormalities, progressing anemia, and cancer predisposition, particularly of oral cancers. These tumors are difficult to manage as FA-patients are sensitive to cross-linking agents such as cisplatin, hampering clinical management of tumors, and for these patients surveillance and prevention is key. Tumors in the head and neck region develop in premalignant mucosal changes, large epithelial areas characterized by cancer-associated genetic changes, also referred to as "fields". These precancerous fields can be centimeters in size, and are often macroscopically invisible. A minority manifests as visible mucosal lesions known as leukoplakia or erythroplakia, which occur with a prevalence of around 0.1-0.2% for leukoplakia 3 , and 0.02-0.2% for erythroplakia 4. Every year, 1-2% of the leukoplakia lesions progress into cancer, and erythroplakia lesions inevitably progress. Despite the occurrence and prevalence of these visible lesions, the large majority of head and neck cancers develop de novo. In resected tumor specimen, however, preceding premalignant changes can be often identified in the surgical margins by either microscopic detection of dysplasia or by ge...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Harten

Boer

Kemp

et al. 2020

Sci Rep

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“…We would thus like to refer the reader to two previous review articles [10,11]. Since immortalized HNSCC cell lines can be easily maintained and expanded, they have broadly been used to study genetic alterations and biological responses to chemical and genetic perturbations, to identify potential molecular targets, and to develop novel small-molecule and biological therapeutics [12,13]. More recently, evidence has been provided that these cell lines can also be used for studying intratumoral heterogeneity and clonal evolution occurring under therapy pressure [14].…”

Section: Ex Vivo Models Immortalized Hnscc Cell Linesmentioning

confidence: 99%

Preclinical models of head and neck squamous cell carcinoma for a basic understanding of cancer biology and its translation into efficient therapies

2020

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Comprehensive molecular characterization of head and neck squamous cell carcinoma (HNSCC) has led to the identification of distinct molecular subgroups with fundamental differences in biological properties and clinical behavior. Despite improvements in tumor classification and increased understanding about the signaling pathways involved in neoplastic transformation and disease progression, current standard-of-care treatment for HNSCC mostly remains to be based on a stage-dependent strategy whereby all patients at the same stage receive the same treatment. Preclinical models that closely resemble molecular HNSCC subgroups that can be exploited for dissecting the biological function of genetic variants and/or altered gene expression will be highly valuable for translating molecular findings into improved clinical care. In the present review, we merge and discuss existing and new information on established cell lines, primary two-and three-dimensional ex vivo tumor cultures from HNSCC patients, and animal models. We review their value in elucidating the basic biology of HNSCC, molecular mechanisms of treatment resistance and their potential for the development of novel molecularly stratified treatment.

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“…Discovery and preclinical testing of new cancer treatments for FA patients is also dependent on the availability of clinical specimens for basic research purposes, which are rather scarce in the case of rare diseases such as FA. As only a handful of HNSCC cell lines derived from FA patients exists worldwide, and the characteristics of the cell lines including the genetic information and the sensitivity profiles to anticancer compounds are largely unknown (Montanuy et al, 2020, van Harten et al, 2019, van Zeeburg et al, 2005, we propose in this report to use genetic engineering on well-established HNSCC cell lines in order to generate new FA-deficient cell line models for studying FA-HNSCC. The main advantages of using such engineered FA cell lines are that their molecular aberrations (Ghandi et al, 2019) (Martin et al, 2014) and sensitivity profiles to many compounds have already been determined (Barretina et al, 2012) and in vivo xenograft models established (Palacios-Garcia et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Generating new FANCA-deficient HNSCC cell lines by genomic editing recapitulate the cellular phenotypes of Fanconi anemia

Errazquin

Sieiro²,

Moreno³

et al. 2020

Preprint

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Fanconi anemia (FA) patients have an exacerbated risk of head and neck squamous cell carcinoma (HNSCC). Treatment is challenging as FA patients display enhanced toxicity to standard treatments, including radio/chemotherapy. Therefore better therapies as well as new disease models are urgently needed. We have used CRISPR/Cas9 editing tools in order to interrupt the human FANCA gene by the generation of insertions/deletions (indels) in exon 4 in two cancer cell lines from sporadic HNSCC having no mutation in FA-genes: CAL27 and CAL33 cells. Our approach allowed efficient editing, subsequent purification of single-cell clones, and Sanger sequencing validation at the edited locus. Clones having frameshift indels in homozygosis did not express FANCA protein and were selected for further analysis. When compared with parental CAL27 and CAL33, FANCA-mutant cell clones displayed a FA-phenotype as they i) are highly sensitive to DNA interstrand crosslink (ICL) agents such as mitomycin C (MMC) or cisplatin, ii) do not monoubiquitinate FANCD2 upon MMC treatment and therefore iii) do not form FANCD2 nuclear foci, and iv) they display increased chromosome fragility and G2 arrest after diepoxybutane (DEB) treatment. These FANCA-mutant clones display similar growth rates as their parental cells. Interestingly, mutant cells acquire phenotypes associated with more aggressive disease, such as increased migration in wound healing assays. Therefore, CAL27 and CAL33 cells with FANCA mutations are phenocopies of FA-HNSCC cells.

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Characterization of a head and neck cancer-derived cell line panel confirms the distinct TP53-proficient copy number-silent subclass

Cited by 26 publications

References 37 publications

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Preclinical models of head and neck squamous cell carcinoma for a basic understanding of cancer biology and its translation into efficient therapies

Generating new FANCA-deficient HNSCC cell lines by genomic editing recapitulate the cellular phenotypes of Fanconi anemia

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