Head and neck cancers continue to rank among the deadliest cancer types despite improvements in the genomics of these tumors, and there aren’t many targeted treatments for them. Intramuscular heterogeneity, the presence of multiple subpopulations of cells with distinct genomic and molecular alterations, and the fact that some cells are inherently more resistant to specific treatments, present a significant challenge in the development of effective treatments.
The activation of mTORC1 by b-catenin / CBP as an upstream driver of the malignancy-associated partial epithelial-mesenchymal transition ( p – EMT ) phenotype was discovered in a recent study from researchers at Boston University Chobanian & amp, Avedisian School of Medicine. The study used advanced bioinformatics and machine learning approaches to analyze large multi-omics head and neck cancer datasets.
EMT is a biological process that is essential for the development of embryos, the repair of tissues, and the treatment of many diseases, including cancer. In cancer, EMT refers to the transformation of mesenchymal cells into epithelial cells, which are more migratory and invasive and are typically found in the outer layers of organs.
This is particularly interesting because p-EMT is a cellular process that is an early predictor of nodal metastasis, in which epithelial cells exhibit characteristics of mesenchymal cells but do not fully undergo the transition. Both mTORC1 and b-cateninare significant cancer hallmarks.
Stefano Monti, PhD, associate professor of medicine at the School of Medicine and co-author
The study’s ultimate objective was to identify potential vulnerabilities that could be therapeutically targeted in order to better characterize oral tumor heterogeneity, including the aggressive cell subpopulations more likely to drive the early stages of cancer progression and invasiveness. According to Monti, comprehending and addressing the various characteristics of tumors can help optimize therapeutic approaches, enhance treatment outcomes, and ultimately increase patient survival rates.
In this collaborative, multidisciplinary study, single cell data from primary oral cancer lesions were analyzed using cutting-edge computational techniques. The Cancer Genome Atlas ( TCGA ) and the Cancer Cell Line Encyclopedia( CCLE ) were used as independent multi-omics datasets to validate the findings. The findings were then further validated through functional molecular and pharmacologic perturbations using cell line-based experiments, as well as through experimental models’ experiments involving drug perturbation.
Given the mounting evidence pointing to a crucial role played by cells with the p-EMT phenotype in tumor progression to advanced disease and the new knowledge about potential therapeutic targets for this malignancy, the study’s findings are of particular timely significance. The study’s findings, in particular, suggest that – catenin / CBP inhibition has the potential to be a promising head and neck cancer treatment that specifically targets more aggressive cells with elevated levels of cystein / cBBP activity.
The findings of this study are primarily focused on head and neck cancer of the oral cavity, but the researchers think they may also apply to other types of cancer, particularly those that are caused by mucosal tissues that line the genital, gastrointestinal, and respiratory tracts.
BU Chobanian & amp, Avedisian School of Medicine researchers Maria A. Kukuruzinska( PhD ), Xaralabos G. Varelas, PhD, professor of biochemistry andamp; cell biology; and Eric Reed, Ph.D., both from Tufts University, are the study’s co-authors.
These results are published online in the Translational Research journal.
This study was funded by NIH grants 5 R01 DE030350( SM, XV, S1 ) DE031831 ( Sm ), R1 R031413( MVB ), Eisai Co., Ltd. Research Award( MAK ), and ACS Research Scholar Award RSG – 17-138 – 01-CSM( XVB ).