Newswise — (Boston)—Despite significant progress in elucidating the genomic features of head and neck cancers, these types of tumors remain highly lethal and have limited options for targeted therapies. A critical obstacle in developing successful treatments lies in the presence of intratumor heterogeneity, where various subgroups of cells within the tumor exhibit diverse genomic and molecular abnormalities. Consequently, certain cells possess inherent resistance to specific treatments, posing a significant challenge in designing effective therapeutic strategies.
Researchers at the Chobanian & Avedisian School of Medicine, Boston University, conducted a recent study utilizing sophisticated bioinformatics and machine learning techniques to examine extensive multi-omics datasets of head and neck cancer. Their findings revealed that the activation of mTORC1 by b-catenin/CBP serves as a key instigator of the partial epithelial-mesenchymal transition (p-EMT) phenotype associated with malignancy.
EMT, a fundamental biological process, holds significant importance in embryonic development, tissue mending, and various disease conditions, including cancer. Specifically in the context of cancer, EMT signifies the transformation of epithelial cells, typically located in the outer layers of organs with robust cell-cell adhesion, into mesenchymal cells that exhibit enhanced migratory and invasive properties.
Co-corresponding author Stefano Monti, PhD, who serves as an associate professor of medicine at the School of Medicine, emphasized the significance of this finding, noting the importance of both mTORC1 and b-catenin as key cancer hallmarks. Furthermore, he highlighted that the partial epithelial-mesenchymal transition (p-EMT) process, which demonstrates traits of mesenchymal cells within epithelial cells without completing the full transition, serves as an early indicator of nodal metastasis.
The researchers' objective was to enhance the understanding of oral tumor heterogeneity, specifically focusing on the aggressive cell subpopulations responsible for initiating early stages of cancer progression and invasiveness. The ultimate aim was to identify potential vulnerabilities that could be targeted with therapeutic interventions. Co-corresponding author Stefano Monti emphasized the importance of comprehending and addressing the diverse features within tumors, as it can optimize therapeutic approaches, enhance treatment outcomes, and ultimately improve patient survival rates.
In this collaborative, multi-disciplinary study, innovative computational techniques were employed to analyze single-cell data obtained from primary oral cancer lesions. The obtained findings underwent validation in independent multi-omics datasets such as The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). Furthermore, the results were reinforced through functional molecular and pharmacologic perturbations conducted in cell line-based experiments. Additionally, pharmacologic perturbation experiments in experimental models were performed to further validate the findings.
The findings of this study hold significant relevance, particularly considering the mounting evidence highlighting the pivotal role of cells exhibiting a p-EMT phenotype in the progression of tumors towards advanced stages. Moreover, these findings provide novel insights into additional therapeutic targets for addressing this malignancy. Specifically, the study underscores the potential of β-catenin/CBP inhibition as a promising treatment approach for head and neck cancer, specifically targeting the more aggressive cells characterized by heightened β-catenin/CBP activity.
Although the study primarily concentrates on head and neck cancer occurring in the oral cavity, the researchers posit that the findings have potential relevance to other types of cancer, particularly those originating from mucosal tissues lining the respiratory, gastrointestinal, and genital tracts. This suggests that the insights gained from this study could have broader implications for understanding and treating various malignancies.
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 in 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).
RSS