IADR Abstract Archives
Single-Cell Multiomics Reveals Field Cancerization’s Role in Oral Cancer Progression
Objectives: The high morbidity and mortality of oral squamous cell carcinoma (OSCC) is driven by rapid recurrence which occurs at an unappreciated rate, though the underlying mechanisms remain unknown. This work investigates OSCC field cancerization where a “field” of genetically altered but normal-appearing cells surrounding tumors, drive recurrence following primary tumor removal. I hypothesize that these cancer “field” cells possess unique molecular features that promote stem cell renewal, predisposing normal-appearing cells to malignant transformation.
Methods: 1: Identification of “field” cell molecular characteristics with multi-omic single-cell (scRNA-seq+scATAC-seq) and whole genome sequencing (WGS) analysis of 10 patient sample sets (tumor, normal-adjacent “field”, contralateral, and blood).
2: Functional testing of genetic alterations necessary to transform precancerous cells to cancer using orthotopic patient-derived xenograft models.
Results: Patient multiome analysis revealed normal-adjacent “field” stem cells consistently display a distinct shift towards a tumor-specific transcriptional and epigenetic signature which prominently features regulators of the TGF-β pathway, a critical stem cell regulator. Consistent with this transcriptional predisposition, WGS uncovered normal “field” and tumor samples harbor a higher driver mutation burden than contralateral tissue, namely in TP53. Underscoring the role of renewal in tumorigenesis, initial in vivo functional testing demonstrated that overexpression of stem cell regulator HRAS in precancerous cells was sufficient to induce tumor transformation. Leveraging findings from my genomic studies, ongoing work utilizes in vivo screening to identify genes responsible for cancer field cell transformation.
Conclusions: Stem cell renewal plays an integral role in OSCC progression where genetic and epigenetic changes promoting renewal in “field” cells likely predispose patients to higher rates of recurrence. Extending this work, I will identify field cancerization biomarkers and validate the role of stem cell regulation in OSCC progression using ex vivo cell fate tracing. Collectively, this research will identify mechanisms regulating transformation of the genetically primed “field” to identify novel therapeutics to prevent recurrence.
Methods: 1: Identification of “field” cell molecular characteristics with multi-omic single-cell (scRNA-seq+scATAC-seq) and whole genome sequencing (WGS) analysis of 10 patient sample sets (tumor, normal-adjacent “field”, contralateral, and blood).
2: Functional testing of genetic alterations necessary to transform precancerous cells to cancer using orthotopic patient-derived xenograft models.
Results: Patient multiome analysis revealed normal-adjacent “field” stem cells consistently display a distinct shift towards a tumor-specific transcriptional and epigenetic signature which prominently features regulators of the TGF-β pathway, a critical stem cell regulator. Consistent with this transcriptional predisposition, WGS uncovered normal “field” and tumor samples harbor a higher driver mutation burden than contralateral tissue, namely in TP53. Underscoring the role of renewal in tumorigenesis, initial in vivo functional testing demonstrated that overexpression of stem cell regulator HRAS in precancerous cells was sufficient to induce tumor transformation. Leveraging findings from my genomic studies, ongoing work utilizes in vivo screening to identify genes responsible for cancer field cell transformation.
Conclusions: Stem cell renewal plays an integral role in OSCC progression where genetic and epigenetic changes promoting renewal in “field” cells likely predispose patients to higher rates of recurrence. Extending this work, I will identify field cancerization biomarkers and validate the role of stem cell regulation in OSCC progression using ex vivo cell fate tracing. Collectively, this research will identify mechanisms regulating transformation of the genetically primed “field” to identify novel therapeutics to prevent recurrence.