Document text
Principal Investigator: Hui Shen
Organization: VAN ANDEL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $353,999
Funding agency: National Cancer Institute
PROJECT SUMMARY / ABSTRACT
OC is the deadliest gynecological cancer in the US. It consists of several histotypes, each biologically distinct
with different clinical challenges. In the first three and half years of the parent grant, in spite of challenges
imposed by COVID, we were able to make substantial progress towards completion of all Aims. We have
published or submitted four papers, with three more to be submitted soon. We were able to develop novel
technologies, new bioinformatics tools, generate and analyze epigenomic and transcriptomic data as planned.
In particular, we discovered that clear cell ovarian cancer (CCOC) and endometrioid ovarian cancer (ENOC),
two closely related OC histotypes, resemble normal endometrial cells at different menstrual cycle phases
(proliferative/follicular, secretory/luteal). Traditionally, the cell-of-origin and accumulated genetic mutations are
viewed as the most important determinants in initiation and development of cancer. However, this dogma does
not apply to the case of CCOC and ENOC, in that both ovarian cancer subtypes arise from the same cell-of-
origin (ectopic endometrium/endometrial-like cells) and share common genetic mutations (ARID1A, PIK3CA,
KRAS), yet demonstrate drastic differences in cellular phenotype and clinical behavior. Through the case of
ENOC and CCOC, we were able to show how cell state (as opposed to cell type) is an underappreciated notion
in the discussion of cell of origin, and how non-genetic mechanisms (epigenetic and transcriptional) regulate this
process. We also observed substantial molecular heterogeneity in the microdissected tumor compartment,
particularly high-grade serous ovarian cancer (HGSOC), suggesting the presence of significant intratumoral
cellular heterogeneity in primary human tumors, an issue the parent grant cannot sufficiently address. Therefore,
we propose to examine single-cell variations of non-epigenetic regulators of cellular states in primary human OC
samples, with novel technologies developed during the parent grant.
Terms: <ARID1A><ARID1A gene><AT- rich interactive domain-containing protein 1A><AT-rich interactive domain 1A gene><Address><Antioncogene Protein p53><Area><Assay><BRCA1><BRCA1 Gene Product><BRCA1 Protein><BRCA1 gene><Basal Transcription Factor><Basal transcription factor genes><Base Pairing><Behavior><Binding Sites><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Breast Cancer 1 Gene><Breast Cancer 1 Gene Product><Breast Cancer Type 1 Susceptibility Gene><Breast Cancer Type 1 Susceptibility Protein><Breast-Ovarian Cancer Protein><C-K-RAS><COVID-19><CV-19><Cancer Patient><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Tumor Antigen P53><Chromatin><Clear Cell><Clinical><Clinical Management><Codependence><Codependency><Combining Site><Coronavirus Infectious Disease 2019><DNA><DNA Alteration><DNA Methylation><DNA Sequence Alteration><DNA mutation><Data><Deoxyribonucleic Acid><Development><Diagnosis><Disease><Disorder><Early Onset Gene Breast Cancer 1><Early Onset Protein Breast Cancer 1><Endometrial><Endometrioid Adenocarcinoma of the Ovary><Endometrioid Cancer of the Ovary><Endometrioid Carcinoma of the Ovary><Endometrium><Enhancers><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial ovarian cancer><Female Reproductive Cancer><Freezing><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genetic mutation><Gynecologic Cancer><Gynecological Cancer><Hereditary Breast Cancer 1><Heterogeneity><Human><Hybrids><Individual><Intracellular Communication and Signaling><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Laser Electromagnetic><Laser Radiation><Lasers><Malignant Cell><Malignant Female Reproductive System Neoplasm><Malignant Gynecologic Neoplasm><Malignant Gynecologic Tumor><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Female Reproductive System><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Maps><Menstrual cycle><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methylation><Modern Man><Molecular><Mutation><NOME-seq><Neoplasm Metastasis><Oncogene K-Ras><Oncogenic><Oncoprotein p53><Ovarian Clear Cell Cancer><Ovarian Clear Cell Carcinoma><Ovarian Clear Cell Neoplasm><Ovarian Clear Cell Tumor><Ovarian Endometrioid Adenocarcinoma><Ovarian Endometrioid Cancer><Ovarian Endometrioid Carcinoma><Ovarian Serous Neoplasm><Ovarian Serous Tumor><Ovary Cancer><P53><PI3K-Alpha><PIK3-Alpha><PIK3CA><PIK3CA gene><Paper><Parents><Phase><Phenotype><Phosphatidylinositol 3-Kinase, Catalytic, 110-kD, Alpha><Phosphatidylinositol 3-Kinase, Catalytic, Alpha><Phosphoprotein P53><Phosphoprotein pp53><Platinum><Platinum Black><Process><Prognosis><Protein TP53><Pt element><Publishing><RASK2><RNA Expression><RNA Seq><RNA sequencing><RNAseq><RNF53><Reactive Site><Regulatory Element><Research><Research Priority><Research Specimen><Resistance development><Resistant development><Resolution><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Sequence Alteration><Serous><Signal Transduction><Signal Transduction Systems><Signaling><Specimen><Standardization><TCGA><TP53><TP53 gene><TRP53><Technology><The Cancer Genome Atlas><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Tumor Cell><Tumor Protein p53><Tumor Protein p53 Gene><United States><Uterine lining><Variant><Variation><base><bases><bio-informatics tool><bioinformatics tool><biological signal transduction><bisulfite><brca 1 gene><cancer cell><cancer metastasis><cancer sub-types><cancer subtypes><cell type><chemotherapy><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cost effective><developing resistance><developmental><endometriosis><epigenetically><epigenome><epigenomics><genome mutation><genome scale><genome-wide><genomewide><genomic alteration><global gene expression><global transcription profile><gynecologic malignancy><gynecological malignancy><hydrogen sulfite><hydrosulfite><interest><malignancy><neoplasm/cancer><neoplastic cell><new technology><non-genetic><nongenetic><novel><novel technologies><nucleosome occupancy and methylome sequencing><ovarian cancer><ovary serous neoplasm><ovary serous tumor><p110-Alpha><p53 Antigen><p53 Genes><p53 Tumor Suppressor><parent><parent grant><promoter><promotor><protein p53><resolutions><single cell technology><social role><transcription factor><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcriptomics><tumor><tumor cell metastasis><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog>