Despite advances in defining the genomic characteristics of head and neck cancers, these malignancies proceed to rank among the many deadliest cancers with few targeted therapies available. A crucial challenge in designing effective treatments is intratumor heterogeneity, the presence of multiple subpopulations of cells with distinct genomic and molecular alterations, with some cells inherently more immune to certain treatments.

A latest study from researchers at Boston University Chobanian & Avedisian School of Medicine applied advanced bioinformatics and machine learning approaches to the evaluation of huge multi-omics head and neck cancer datasets and located activation of mTORC1 by b-catenin/CBP as an upstream driver of the malignancy-associated partial epithelial-mesenchymal transition (p-EMT) phenotype.

EMT is a biological process that plays a vital role in embryonic development, tissue repairand various disease processes, including cancer. In cancer, EMT refers back to the conversion of epithelial cells, that are typically present in the outer layers of organs and have strong cell-cell adhesion, into mesenchymal cells, that are more migratory and invasive.

That is of particular interest because each mTORC1 and b-cateninare essential cancer hallmarks and p-EMT is a cellular process that’s an early predictor of nodal metastasis, through which epithelial cells manifest characteristics of mesenchymal cells but don’t fully undergo the whole transition.”

Stefano Monti, PhD, co-corresponding writer, associate professor of drugs on the School of Medicine

In response to the researchers, the study aimed to raised characterize oral tumor heterogeneity including the aggressive cell subpopulations more more likely to drive the early steps in cancer progression and invasiveness, with the last word goal of identifying candidate vulnerabilities that could possibly be targeted therapeutically. “Understanding and addressing the varied characteristics inside tumors will help optimize therapeutic strategies, improve treatment outcomes and ultimately enhance patient survival rates,” said Monti.

This collaborative multi-disciplinary study applied novel computational methods to the evaluation of single cell data from primary oral cancer lesions. Findings were first validated in independent multi-omics datasets, including The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), then further validated through functional molecular and pharmacologic perturbations using cell line-based experiments, in addition to through pharmacologic perturbation experiments in experimental models.

The study’s findings are of particularly timely significance, given the increasing evidence pointing to a vital role of cells with a p-EMT phenotype in tumor progression to advanced disease and supply latest details about additional therapeutic targets for this malignancy. Specifically, the study’s findings point to the potential of β-catenin/CBP inhibition as a promising head and neck cancer treatment that distinctly targets more aggressive cells with elevated β catenin/CBP activity.

While this study’s findings give attention to head and neck cancer of the oral cavity, the researchers consider they’re more likely to be relevant to other cancer types, especially people who arise from mucosal tissues that line respiratory, gastrointestinal and genital tracts.

The co-corresponding authors on this study are BU Chobanian & Avedisian School of Medicine researchers Maria A. Kukuruzinska, PhD, professor of molecular & cell biology; Xaralabos G. Varelas, PhD, professor of biochemistry & cell biology and Eric Reed, PhD, from Tufts University.

These findings appear online within the journal Translational Research.

Funding for this study was supported by NIH grants 5 R01 DE030350 (MAK, SM, XV), R01 DE030350 S1 (SM), R01 DE031831 (SM), R01 DE031413 (MVB), ACS Research Scholar Award RSG-17-138-01-CSM (XV), and Eisai Co., Ltd Research Award (MAK).

Source:

Boston University School of Medicine

Journal reference:

Reed, E. R., et al. (2023) β-catenin/CBP activation of mTORC1 signaling promotes partial epithelial-mesenchymal states in head and neck cancer. Translational Research. doi.org/10.1016/j.trsl.2023.05.007.