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Genome-wide CRISPR screen identifies AMBRA1 as a potential biomarker of response to platinum-based therapies in oral squamous cell carcinomas [CRISPR Screen]

ABSTRACT: Oral Squamous Cell Carcinomas (OSCC) are among the most frequent and lethal cancers worldwide. Advanced stage tumors are still treated with standard chemotherapy, however, most of the patients develop chemotherapy resistance. To uncover new functional biomarkers of cisplatin response, we performed a synthetic lethality genome wide CRISPR/Cas9 screen in an oral squamous cell carcinoma cell line. This led to the discovery of AMBRA1, as a regulator of cisplatin sensitivity. In all tested OSCC cell lines and oral primary cultures, AMBRA1 knockout cells showed increased sensitivity to cisplatin treatment. Mechanistically, we demonstrated a new function of AMBRA1, where loss of AMBRA1 led to higher S phase, higher expression of genome instability markers, and higher DNA damage in basal conditions, thereby predisposing cancer cells to an increased sensitivity to cisplatin as well as to other platinum drugs. In summary, we uncovered AMBRA1 as a potential biomarker of response to platinum-based therapies in oral squamous cell carcinomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE333513 | GEO | 2026/06/03

REPOSITORIES: GEO

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Project description:Differentially methylated oral squamous cell carcinoma (OSCC) biomarkers, identified in-vitro and validated in well-characterized surgical specimens, have shown poor clinical correlation in cohorts with different risk profiles. To overcome this lack of relevance we used the HumanMethylation27 BeadChip, publicly available methylation and expression array data, and Quantitative Methylation Specific PCR to uncover differential methylation in OSCC clinical samples with heterogeneous risk profiles. A two stage-design consisting of Discovery and Prevalence screens was used to identify differential promoter methylation and deregulated pathways in patients diagnosed with OSCC and head and neck squamous cell carcinoma. Promoter methylation of KIF1A (k=0.64), HOXA9 (k=0.60), NID2 (k=0.60), and EDNRB (k=0.60) had a moderate to substantial agreement with clinical diagnosis in the Discovery screen. HOXA9 had 68% sensitivity, 100% specificity and a 0.81 AUC. NID2 had 71% sensitivity, 100% specificity and a 0.79 AUC. In the Prevalence screen HOXA9 (k=0.82) and NID2 (k=0.80) had an almost perfect agreement with histologic diagnosis. HOXA9 had 85% sensitivity, 97% specificity and a 0.95 AUC. NID2 had 87% sensitivity, 95% specificity and a 0.91 AUC. A HOXA9 and NID2 gene panel had 94% sensitivity, 97% specificity and a 0.97 AUC. In saliva from OSCC cases and controls HOXA9 had 75% sensitivity, 53% specificity and a 0.75 AUC. NID2 had 87% sensitivity, 21% specificity and a 0.73 AUC. This Phase I Biomarker Development Trial identified a panel of differentially methylated genes in normal and OSCC clinical samples from patients with heterogeneous risk profiles. This panel may be useful for early detection and cancer prevention studies. The 12 samples analyzed comprise equal numbers of three tissue-types: Primary oral squamous cell carcinoma, Oral leukoplakia and Normal oral mucosa. Gender, age and smoking-status were approximately equally represented in these goups. Normal oral mucosa served as a control.

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Genome-wide CRISPR screen identifies AMBRA1 as a potential biomarker of response to platinum-based therapies in oral squamous cell carcinomas [CRISPR Screen]

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