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Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities.

ABSTRACT: Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer. Most patients who develop metastases (2-5%) present with advanced disease that requires a combination of radical surgery and adjuvant radiation therapy. There are few effective therapies for refractory disease. In this study, we describe novel patient-derived cell lines from cSCC metastases of the head and neck (designated UW-CSCC1 and UW-CSCC2). The cell lines genotypically and phenotypically resembled the original patient tumor and were tumorogenic in mice. Differences in cancer-related gene expression between the tumor and cell lines after various culturing conditions could be largely reversed by xenografting and reculturing. The novel drug susceptibilities of UW-CSCC1 and an irradiated subclone UW-CSCC1-R to drugs targeting cell cycle, PI3K/AKT/mTOR, and DNA damage pathways were observed using high-throughput anti-cancer and kinase-inhibitor compound libraries, which correlate with either copy number variations, targetable mutations and/or the upregulation of gene expression. A secondary screen of top hits in all three cell lines including PIK3CA-targeting drugs supports the utility of targeting the PI3K/AKT/mTOR pathway in this disease. UW-CSCC cell lines are thus useful preclinical models for determining targetable pathways and candidate therapeutics.

SUBMITTER: Perry J

PROVIDER: S-EPMC7765308 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities.

Perry Jay J Ashford Bruce B Thind Amarinder Singh AS Gauthier Marie-Emilie ME Minaei Elahe E Major Gretel G Iyer Narayanan Gopalakrishna NG Gupta Ruta R Clark Jonathan J Ranson Marie M

International journal of molecular sciences 20201215 24

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer. Most patients who develop metastases (2-5%) present with advanced disease that requires a combination of radical surgery and adjuvant radiation therapy. There are few effective therapies for refractory disease. In this study, we describe novel patient-derived cell lines from cSCC metastases of the head and neck (designated UW-CSCC1 and UW-CSCC2). The cell lines genotypically and phenotypically resembled the original patient tumor ...[more]

PMID: 33333825

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Project description:ImportanceCutaneous squamous cell carcinoma (cSCC) is the most common skin cancer with metastatic potential, but epidemiologic data are poor. Changes to the National Cancer Registration and Analysis Service (NCRAS) in England have allowed more accurate data analysis of primary and metastatic cSCC since 2013.ObjectiveTo assess the national incidence of cSCC and metastatic cSCC (mcSCC) in England from 2013 through 2015.Design, setting, and participantsThis national population-based study identified a cohort of patients with cSCC and mcSCC in England from January 1, 2013, through December 31, 2015. Patients were identified using diagnostic codes derived from pathology reports in the NCRAS. Data were analyzed from March 1, 2017, through March 1, 2018.Main outcomes and measuresIncidence rates across sex and risk factors for cSCC were derived from the NCRAS data. Risk of occurrence of mcSCC among the population with cSCC was assessed with Cox proportional hazards regression analysis to determine indicators of mcSCC.ResultsAmong the 76 977 patients with first primary cSCC in 2013 through 2015 (62.7% male; median age, 80 years [interquartile range, 72-86 years]), the age-standardized rates for the first registered cSCC in England from 2013 through 2015 were 77.3 per 100 000 person-years (PY) (95% CI, 76.6-78.0) in male patients and 34.1 per 100 000 PY (95% CI, 33.7-34.5) in female patients. Increased primary cSCC tumor count was observed in older, white male patients in lower deprivation quintiles. After a maximum follow-up of 36 months, cumulative incidence of mcSCC developed in 1.1% of women and 2.4% of men with a primary cSCC. Significant increases in the risk of metastasis with adjusted hazard rates of approximately 2.00 were observed in patients who were aged 80 to 89 years (hazard ratio [HR], 1.23; 95% CI, 1.07-1.43), 90 years or older (HR, 1.35; 95% CI, 1.09-1.66), male (HR, 1.79; 95% CI, 1.52-2.10), immunosuppressed (HR, 1.99; 95% CI, 1.64-2.42), and in higher deprivation quintiles (HR for highest quintile, 1.64; 95% CI, 1.35-2.00). Primary cSCC located on the ear (HR, 1.70; 95% CI, 1.42-2.03) and lip (HR, 1.85; 95% CI, 1.29-2.63) were at highest risk of metastasis.Conclusions and relevanceThis study presents the first national study of the incidence of mcSCC. With limited health care resources and an aging population, accurate epidemiologic data are essential for informing future health care planning, identifying high-risk patients, and evaluating skin cancer prevention policies.

Project description:Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3' untranslated region (3'UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of "TGF-beta regulation of extracellular matrix" and "cell cycle G1 to S check points." These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.

Dataset Information

Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities.

Publications

Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities.

Similar Datasets

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