Abstract IA07: Head and neck squamous cell cancer stem cells: Harnessing oncogenic signaling to enable tumorigenicity

Head and neck squamous cell cancer (HNSCC) bear a significant degree of functional intratumor heterogeneity, as evidenced by differential morphology, key protein expression, immune infiltration, as well as response to therapy. Some of these differences can be explained by the ability of HNSCC cells to move along a continuum of plasticity, with a small fraction of cells having higher potential; these can be defined as tumor initiating cells (TICs) or the more broadly used term cancer stem cells (CSCs). We have an incomplete understanding of the key characteristics defining HNSCC CSCs, including the differences between human papillomavirus positive (HPV-positive) and negative (HPV-negative) cases. The PI3K pathway has the most frequent activating genetic events in HNSCC (especially HPV-positive driven), but how CSCs exploit oncogenic signaling between is also unknown. In this review presentation we will summarize the work studying these issues (JNCI 2016, PMID: 27634934), and we will lay out ongoing lines of investigation. In this work we investigated these unresolved issues using CSCs identified from ten HNSCC patient-derived xenografts (PDXs). Sorted populations were then serially passaged in mice to evaluate tumorigenic capacity and tumor reconstitution. HNSCC CSCs and non-CSCs were compared by mRNA-sequencing. To assess another key characteristic of CSCs we compared the susceptibility of CSCs to therapy using an in vivo model. CSCs were defined by high aldehyde dehydrogenase (ALDH) activity and CD44 expression, and were equivalent between HPV-positive and HPV-negative cases. CSCs had PI3K/mTOR pathway over-expression, and PI3K inhibition in vivo decreased their tumorigenicity. PI3K/mTOR regulated SOX2 protein levels, and SOX2 in turn activated ALDH1A1 expression and ALDH activity in HNSCC. SOX2 expression generated a CSC-like population in early passage HNSCC cells, in a proportion similar to that found in vivo. SOX2 expression enhanced sphere and tumor growth and therapy resistance. SOX2 expression prompted mesenchymal to epithelial transition (MET) by inducing CDH1, followed by asymmetric division and proliferation, which contributed to tumor formation. In the drug studies we evidenced differential susceptibility of CSCs and non-CSCs sub-populations to both standard and investigational agents, with CSCs being resistant to conventional therapy. SOX2 expression induced drug resistance. We have generated additional pairs of patient-derived cells where the forced expression of SOX2 leads to a CSC phenotype, and are using these models to further study CSC biology and response to therapy, and to explain the intratumor heterogeneity seen in HNSCC. The molecular link between PI3K activation and CSC properties found in our research provides insights into therapeutic strategies for HNSCC. Constitutive expression of SOX2 in HNSCC cells generates a CSC-like population that enables CSC studies. Additional investigations into how CSCs harness oncogenic signals to achieve key cancer characteristics such as immune evasion will be discussed. Citation Format: Antonio Jimeno. Head and neck squamous cell cancer stem cells: Harnessing oncogenic signaling to enable tumorigenicity [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA07.