System-Level Analyses of Multi-Omics Data to Reveal Mechanisms of Head & Neck Cancer
Project Number5R01DE031831-03
Contact PI/Project LeaderMONTI, STEFANO
Awardee OrganizationBOSTON UNIVERSITY MEDICAL CAMPUS
Description
Abstract Text
Head and neck squamous cell carcinoma (HNSCC) is a devastating disease with an overall 5-year survival
rate of only ~60%. In part, this high death rate is a result of late disease diagnosis, often with regional lymph
node metastasis. Recent studies, including The Cancer Genome Atlas (TCGA), and the Cancer Cell Line
Encyclopedia (CCLE), mapped genomic alterations in a variety of cancers, and are beginning to provide
insights into the dysregulated signals contributing to the onset and progression of HNSCC, but there has been
only modest improvement in therapeutic strategies. This lack of progress is partly due to a lack of mechanistic
understanding of the signals that drive malignant transformation.
Prior and ongoing studies carried out in our laboratories have identified multiple homeostatic pathways whose
deregulation contributes to HNSCC HPV(-) initiation, development and progression. In particular, we have
shown that pharmacologic inhibition of the interaction between 𝛽𝛽-catenin and the histone acetyltransferase
cAMP-responsive element binding (CREB)-binding protein (CBP) inhibits HNSCC cell proliferation and CSC
phenotypes, and reduces invasive traits. Conversely, we showed that elevated β-catenin/CBP signaling in
primary HNSCC tumors was associated with tumor progression and poor patient survival. We also showed a
strong association between WNT/𝛽𝛽-catenin, the oncogenic activity of the paralogous transcriptional regulators
YAP and TAZ (YAP/TAZ), and of mTOR, suggesting interactions between these pathways.
Thus, our proposal seeks to elucidate, through computational approaches, the molecular links between
somatic variation, the activity of selected homeostatic pathways (𝛽𝛽-catenin/CBP, TAZ/YAP, mTOR and others),
and EMT and CSC phenotypes in early and advanced stages of HNSCC. To achieve this goal, we will perform
integrative analyses of public multi-omics datasets from human and mouse, leveraging our newly developed
methods of taxonomy discovery and gene regulatory network (GRN) inference. Application of these methods
will allow us to identify important network hubs and regulators, and how their connectivity changes in response
to perturbation or between phenotypic groups and disease stages. The hypotheses generated will be validated
in in-vitro and in-vivo models we have developed in our laboratories. The results of our analyses will support
the identification of novel candidate drivers of the disease amenable to therapeutic targeting. Three aims are
thus proposed. First, we will analyze publicly available multi-omics datasets from human HNSCC, including
bulk and single-cell RNAseq profiles, proteomics and methylomics profiles, and paired somatic copy number
alterations (SCNAs) and mutations. Second, we will analyze bulk- and sc-RNAseq profiles from premalignant
lesions in mouse and human, including profiles from mice treated with small molecule 𝛽𝛽-catenin/CBP inhibitors.
Finally, we will share all our tools and results through well-documented Bioconductor packages and interactive
web-based portals, which will allow other investigators to use the generated resources in their research.
Public Health Relevance Statement
In this proposal, we will investigate mechanisms of oral cancer initiation and progression for the identification of
novel candidate drivers of the disease amenable to therapeutic targeting. We will apply system-level
computational approaches, including novel taxonomy discovery and Markov network inference and comparison
methods, to analyze existing multi-omics mouse and human datasets. Our primary, yet not exclusive, focus will
be on the definition of the molecular links between somatic variation, 𝛽𝛽-catenin/CBP, TAZ/YAP, and mTOR
activity, and EMT and CSC phenotypes in early and advanced stages of OSCC, and the hypotheses we generate
will be evaluated in in-vitro and in-vivo models we have developed in our laboratories.
National Institute of Dental and Craniofacial Research
CFDA Code
121
DUNS Number
604483045
UEI
FBYMGMHW4X95
Project Start Date
17-March-2022
Project End Date
31-January-2026
Budget Start Date
01-February-2024
Budget End Date
31-January-2026
Project Funding Information for 2024
Total Funding
$426,194
Direct Costs
$277,574
Indirect Costs
$148,620
Year
Funding IC
FY Total Cost by IC
2024
National Institute of Dental and Craniofacial Research
$426,194
Year
Funding IC
FY Total Cost by IC
Sub Projects
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