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Principal Investigator: Markus Schober
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $468,096
Funding agency: National Cancer Institute
SUMMARY
Mutations that activate proto-oncogenes or inactivate tumor suppressor genes are the root causes of tumor
initiation, but recent genomic analyses also detect these mutations in many cells of healthy tissues. These data
and classic skin carcinogenesis studies suggest that mutations in proto-oncogenes or tumor-suppressor genes
are tolerated and maintained in epidermal progenitor cells (EPCs) until elusive mechanisms transform these
precancerous cells into stem-cell-like tumor propagating cells (TPCs) that can support tumor formation and
growth. We transcriptionally profiled these TPCs in squamous cell carcinoma (SCC) models and defined a gene
expression signature that distinguishes TPCs from EPCs. Within this signature, we identified the transcription
factors PITX1 and SOX2 in >60% of mouse and human SCCs, even though they are epigenetically repressed
and not detectable in normal skin epithelial cells. We showed PITX1 and SOX2 are required for SCC growth in
mouse and patient-derived SCC models highly enriched on gene regulatory enhancers accessible in TPCs but
not EPCs, and responsible for the expression of SCC signature genes. Although PITX1 and SOX2 are pivotal
for squamous carcinogenesis, it is still unclear what events trigger their de novo expression in TPCs, and whether
their ability to bind condensed (inactive) chromatin and open it to activate SCC-specific gene expression
reprograms EPCs into TPCs. Here, we propose to test the hypothesis that oncogenic RAS and
inflammation together or independently activate RUNX1, which initiates expression of PITX1 and then
SOX2, allowing them to transcriptionally reprogram EPCs into TPCs that promote squamous
carcinogenesis. To test this hypothesis, we propose to: 1) determine whether and how inflammation-induced
RUNX1 activity promotes de novo PITX1 expression in normal and pre-cancerous skin epithelial cells; and 2)
determine whether and how ectopically expressed RUNX1, PITX1, and/or SOX2 reprogram EPCs into TPCs to
promote SCC initiation. To accomplish these aims, we already established genetic gain- and loss-of-function
approaches in autochthonous mouse and human SCC models along with genome-wide analyses (ATAC-seq,
ChIP-seq, 4C-seq, RNA-seq) and fluorescent transcriptional reporter assays. We are uniquely positioned to
reveal the molecular events that explain: 1) how PITX1 and SOX2 become expressed de novo in mouse and
human SCCs, 2) whether SOX2 and PITX1 establish or use SCC-defining gene regulatory enhancers to control
the expression of SCC signature genes, and 3) how these changes in gene expression transform precancerous
cells into TPCs that promote squamous carcinogenesis. Our proposed research will provide molecular insights
that promise to guide the development of approaches to prevent or treat SCCs in patients and/or define
mechanisms that may promote the initiation of other cancers including but not limited to lung, esophageal, and
pancreatic SCCs, which are among the most common deadly cancers.
Terms: <3C-based approach><3C-based assay><3C-based method><3C-based strategy><3C-based technique><3C-based technology><4C-seq><AML1><AMLCR1><ATAC sequencing><ATAC-seq><ATACseq><Anti-Oncogenes><Antioncogenes><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioassay><Biological Assay><Body Tissues><CBFA2><Cancer Induction><Cancer Suppressor Genes><Cancers><Carcinoma><Carcinoma Cell><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Cellular Oncogene><ChIP Sequencing><ChIP assay><ChIP-seq><ChIPseq><Chemicals><Chromatin><Chromatin Conformation Capture and Sequencing><Clonal Expansion><Cutaneous><Data><Development><Disease><Disorder><Emerogenes><Enhancers><Epidermoid Carcinoma><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Epithelial cancer><Esophagus><Event><Expression Signature><Gene Expression><Gene Expression Profile><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomics><Growth><Heterogeneity><Human><Inflammation><Intracellular Communication and Signaling><Link><Lung><Lung Respiratory System><Malignant Cell><Malignant Epithelial Cell><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasms><Malignant Tumor><Measures><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Murine><Mus><Mutation><Mutation Detection><Nucleus><Onco-Suppressor Genes><Oncogenes-Tumor Suppressors><Oncogenic><PEBP2A2><PEBP2aB><Pancreas><Pancreatic><Patients><Phosphorylation><Physiologic><Physiological><Planocellular Carcinoma><Position><Positioning Attribute><Precancerous Cells><Premalignant Cell><Process><Progenitor Cells><Protein Phosphorylation><Proto-Oncogenes><RNA Expression><RNA Seq><RNA sequencing><RNAseq><RUNX1><RUNX1 gene><Recessive Oncogenes><Regulatory Element><Reporter><Repression><Research><Resected><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skin><Skin Carcinogenesis><Squamous Carcinoma><Squamous Cell Epithelioma><Squamous Differentiation><Squamous cell carcinoma><Stem Cell like><Testing><Therapeutic><Tissue Growth><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription Initiation><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transducers><Tumor Promotion><Tumor Suppressing Genes><Tumor Suppressor Genes><United States><Visualization><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biological signal transduction><c-ONC><cancer cell><carcinogenesis><cell transformation><check point inhibition><checkpoint inhibition><chromatin conformation capture><chromatin immunoprecipitation><chromatin immunoprecipitation-sequencing><chromosome capture><chromosome conformation capture><conformation><conformational><conformational state><conformationally><conformations><cutaneous carcinogenesis><developmental><epidermal progenitor><epidermal progenitor cell><epidermal stem cell><epigenetically><epithelial carcinoma><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><gain of function><gene expression pattern><gene expression signature><gene signatures><genetic signature><genome mutation><genome wide analysis><genome wide studies><genome-wide analysis><genome-wide identification><global gene expression><global transcription profile><human model><immune check point inhibition><immune checkpoint inhibition><improved><insight><loss of function><malignancy><model of human><mouse model><murine model><neoplasm/cancer><new approaches><novel approaches><novel strategies><novel strategy><oncosuppressor gene><ontogeny><organ transplant patient><organ transplant recipient><precancer><precancerous><premalignant><prevent><preventing><programs><promoter><promotor><protooncogene><pulmonary><response><self-renew><self-renewal><social role><stem cell characteristics><stem cells><stemness><tissue wound><transcription factor><transcriptional profile><transcriptional reprogramming><transcriptional signature><transcriptome><transcriptome sequencing><transcriptomic sequencing><transformed cells><tumor><tumor growth><tumor initiation><wound><wounding><wounds>