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Principal Investigator: Markus Schober
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $437,810
Funding agency: National Cancer Institute
SUMMARY
SOX2 is a cell fate–determining transcription factor that is expressed in ~70% of cutaneous and head and neck
squamous cell carcinomas (SCCs) in patients. SOX2 is highly enriched in stem cell–like tumor-propagating cells
(TPCs), which are located within the basal SCC layer where they can self-renew or differentiate into suprabasal
SCC cells without proliferative potential. Although we know SOX2 controls the fate choice between TPC self-
renewal and squamous differentiation, it is unclear how its activity is regulated in SCCs and whether these
regulatory mechanisms could be developed into therapies for cancer patients. Here, we propose to test the
hypothesis that phosphorylation of SOX2 inhibits its activity, perturbs the SCC-specific SOX2-PITX1-
TP63 self-renewal circuit that drives clonal expansion and SCC growth, and thereby restores the KLF4-
dependent squamous differentiation program in SCCs. Our hypothesis is based on our preliminary studies,
which showed that SOX2 can be phosphorylated and that this phosphorylation attenuates its activity in SCC
cells. We propose to 1) test if SOX2 phosphorylation inhibits TPC self-renewal, clonal expansion, and SCC
growth; 2) identify the kinases and phosphatases that regulate SOX2 phosphorylation and function; and 3) define
the molecular mechanisms by which SOX2 activity governs TPC self-renewal, SCC growth, and differentiation
in mouse and patient-derived SCC models. We expect our proposed research will explain the fate choice
between TPC self-renewal and terminal differentiation on a molecular level and therefore provide new concepts
for the rational development of pharmacological approaches that enforce the commitment of TPCs to terminally
differentiate into SCC cells without proliferative potential.
Terms: <Ablation><Acceleration><Affect><Anti-Rejection Therapy><Assay><Attenuated><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological Assay><Bone Sarcoma><CDK5><CDK5 gene><Cancer Induction><Cancer Patient><Cancer Treatment><Cancers><Carcinoma Cell><Cell Body><Cell Division Kinase 5 Gene><Cell Nucleus><Cells><ChIP Sequencing><ChIP-seq><ChIPseq><Checkpoint inhibitor><Chromatin><Clonal Expansion><Closure by Ligation><Co-Immunoprecipitations><Complex><Cutaneous><Cutaneous Squamous Cell Carcinoma><Data><Development><Disease><Disorder><Enhancers><Epidermoid Carcinoma><Epidermoid Cell Lung Carcinoma><Epidermoid Skin Carcinoma><Epithelial Cells><Esophageal Cancer><Esophagus Cancer><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Glioblastoma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Growth><HNSCC><Head and Neck Squamous Cell Carcinoma><Human><Immune checkpoint inhibitor><Immunoblotting><Immunosuppressive Therapy><KI mice><Kinases><Knock-in Mouse><Ligation><Malignant Epithelial Cell><Malignant Esophageal Neoplasm><Malignant Esophageal Tumor><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Esophagus><Malignant Tumor of the Lung><Malignant neoplasm of esophagus><Malignant neoplasm of lung><Measures><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Murine><Mus><Mutation><Nucleus><Oncogenic><Osseous Sarcoma><Osteogenic Sarcoma><Osteosarcoma><PDX model><Patient derived xenograft><Patients><Pattern><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphorylation><Phosphorylation Inhibition><Phosphotransferase Gene><Phosphotransferases><Planocellular Carcinoma><Protein Phosphorylation><Publishing><Pulmonary Cancer><Pulmonary malignant Neoplasm><RNA Expression><Recurrence><Recurrent><Regulation><Repression><Research><Resected><SCCHN><Skeletal Sarcoma><Skin><Squamous Carcinoma><Squamous Cell Epithelioma><Squamous Cell Lung Carcinoma><Squamous Differentiation><Squamous cell carcinoma><Squamous cell lung cancer><Stem Cell like><Testing><Therapeutic immunosuppression><Tissue Growth><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transphosphorylases><United States><Western Blotting><Western Immunoblotting><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><anti-cancer therapy><artificial immunosuppression><attenuate><attenuates><cancer therapy><cancer-directed therapy><carcinogenesis><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><chromatin immunoprecipitation-sequencing><developmental><genome mutation><glioblastoma multiforme><head and neck squamous carcinoma><head and neck squamous cell cancer><hormone refractory prostate cancer><immune check point inhibitor><immunosuppression therapy><knockin mice><lung cancer><lung squamous cancer><lung squamous carcinoma><lung squamous cell carcinoma><malignancy><mimetics><mouse model><murine model><mutant><neoplasm/cancer><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><oesophageal cancer><ontogeny><organ transplant patient><organ transplant recipient><osteochondrosarcoma><osteoid sarcoma><patient derived xenograft model><pharmacologic><phosphatase inhibitor><prevent><preventing><programs><prostate cancer resistant to androgen><protein blotting><self-renew><self-renewal><single molecule><skin squamous cell carcinoma><spongioblastoma multiforme><squamous cell carcinoma of the lung><stem cell characteristics><stemness><tandem mass spectrometry><transcription factor><tumor>