Identification of lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver for invasion and migration of oral cancer by tumor heterogeneity exploitation

Abstract

Background Cancer metastases are the main cause of lethality. The five-year survival rate for patients diagnosed with advanced stage oral cancer is 30%. Hence, the identification of novel therapeutic targets is an urgent need. However, tumors are comprised of a heterogeneous collection of cells with distinct genetic and molecular profiles that can differentially promote metastasis making therapy development a challenging task. Here, we leveraged intratumoral heterogeneity in order to identify drivers of cancer cell motility that might be druggable targets for anti-metastasis therapy. Methods We used 2D migration and 3D matrigel-based invasion assays to characterize the invasive heterogeneity among and within four human oral cancer cell lines in vitro. Subsequently, we applied mRNA-sequencing to map the transcriptomes of poorly and strongly invasive subclones as well as primary tumors and matched metastasis. Results We identified SAS cells as a highly invasive oral cancer cell line. Clonal analysis of SAS yielded a panel of 20 subclones with different invasive capacities. Integrative gene expression analysis identified the Lymphocyte cell-specific protein-tyrosine kinase (LCK) as a druggable target gene associated with cancer cell invasion and metastasis. Inhibition of LCK using A-770041 or dasatinib blocked invasion of highly aggressive SAS cells. Interestingly, reduction of LCK activity increased the formation of adherens junctions and induced cell differentiation. Conclusion Analysis of invasive heterogeneity led to the discovery of LCK as an important regulator of motility in oral cancer cells. Hence, small molecule mediated inhibition of LCK could be a promising anti-metastasis therapy option for oral cancer patients.

Multifunctions of CRIF1 in cancers and mitochondrial dysfunction

“…In addition, CRIF1 function is inhibited by interacting with lymphocyte-specific protein tyrosine kinase (Lck) and leads to promotion of leukemic T-cell survival. Lck, which belongs to Src family kinases (SFKs), is universally expressed in T cells and easily detected in blood malignancies and many other solid tumors ( 62 – 64 ). In hepatocellular carcinoma (HCC), CRIF1 is beneficial to patient survival.…”

Lucidenic acid A inhibits the binding of hACE2 receptor with spike protein to prevent SARS-CoV-2 invasion

“…hACE2 can affect the expression of TP53 in pulmonary endothelial cells, and the deletion of TP53 binding site leads to the enhancement of hACE2 promoter activity ( Zhang et al, 2021 ). LCK gene is a member of the protein tyrosine kinase family, and the encoded protein is a key signal molecule for T cell selection and maturation in development ( Weiße et al, 2021 ). IL6 encodes a cytokine that plays a role in inflammation and B cell maturation, which can cause fever in patients with autoimmune diseases or infections, mainly acute and chronic inflammation ( Dolsen and Harvey, 2021 ).…”

Molecular profiling of core immune-escape genes highlights LCK as an immune-related prognostic biomarker in melanoma

“…In addition, a growing number of studies have shown that LCK is also expressed in brain and tumor cells, where it is actively involved in the regulation of cellular functions such as proliferation and survival ( 14 , 34 , 35 ). LCK is highly expressed in most cancers, including breast cancer, colorectal cancer and glioma ( 36 – 39 ). We found that the expression level of LCK was significantly higher in melanoma tumor tissues than in normal tissues ( Figure 5C ).…”