Cancer stem cells (CSCs) from oral squamous cell carcinomas (OSCCs) are expected to have properties of self-renewal, metastasis, and treatment resistance. Current model systems for studying CSCs are largely in immune compromised and species-mismatched stromal environments, which do not capture all CSC properties. We have developed """"""""XactMice"""""""" in which human OSCCs are transplanted into mice bearing human hematopoietic stem cells (HSC) that reconstitute human immune cells and other HSC-derived human stroma cells. OSCCs in XactMice exhibited pathological and molecular signatures more similar to primary human OSCCs than OSCCs in immune compromised recipient mice. Additionally, we developed genetically engineered mouse models (GEMMs) with spontaneous OSCCs. Using these complementary models, we will study the influence of the microenvironment on CSC properties, and how this alters treatment resistance. First, we will examine if immune system and species-matched stromal cells affect sizes and behaviors of transplanted CSCs, including cancer initiation, metastasis and resistance to radiation, the main therapy for OSCC. Second, we will combine CSCs in co-culture systems with primary cancer associated fibroblasts (CAFs) or CAFs from XactMice from the same patient, and assess if HSC-derived fibroblasts have the same influence as primary CAFs on CSC self-renewal and invasion, and if a small portion of HSC-derived fibroblasts among mouse fibroblasts is sufficient to contribute to CSC behavioral changes. Finally, based on our preliminary data, we will study if inhibiting TGF? signaling hampers CSC properties of cancer initiation, metastasis and radiotherapy resistance, and identify which TGF? signaling components and targets are involved in CSC regulation. Our efforts to transform human cancer models in which human OSCCs grow in immune competent and species-matched stromal cells provide an ideal platform to study the interaction between CSCs and stroma in OSCC. These experiments will advance understanding of CSC biology, tumor- stroma interactions in human cancer, and the prioritization of novel targeted molecules for inhibiting cancer growth and metastasis.

Public Health Relevance

This proposal will employ our unique model systems in which human or mouse oral cancer stem cells grow in immune competent and species-matched supportive cells (stroma). In these microenvironments that closely mimic naturally occurring human cancer, we will identify cancer stem populations responsible for cancer initiation, treatment resistance and metastasis, and analyze stromal contributions to these processes.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDE1-RK (24))
Program Officer
Venkatachalam, Sundaresan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Schools of Medicine
United States
Zip Code
Keysar, Stephen B; Eagles, Justin R; Miller, Bettina et al. (2018) Salivary Gland Cancer Patient-Derived Xenografts Enable Characterization of Cancer Stem Cells and New Gene Events Associated with Tumor Progression. Clin Cancer Res 24:2935-2943
Dionne, Lai Kuan; Peterman, Eric; Schiel, John et al. (2017) FYCO1 regulates accumulation of post-mitotic midbodies by mediating LC3-dependent midbody degradation. J Cell Sci 130:4051-4062
Keysar, Stephen B; Le, Phuong N; Miller, Bettina et al. (2017) Regulation of Head and Neck Squamous Cancer Stem Cells by PI3K and SOX2. J Natl Cancer Inst 109:
Jian, Zhe; Strait, Alexander; Jimeno, Antonio et al. (2017) Cancer Stem Cells in Squamous Cell Carcinoma. J Invest Dermatol 137:31-37
Morton, J J; Bird, G; Keysar, S B et al. (2016) XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer. Oncogene 35:290-300
Mishra, Ameet K; Kadoishi, Tanya; Wang, Xiaoguang et al. (2016) Squamous cell carcinomas escape immune surveillance via inducing chronic activation and exhaustion of CD8+ T Cells co-expressing PD-1 and LAG-3 inhibitory receptors. Oncotarget 7:81341-81356
Morton, J Jason; Bird, Gregory; Refaeli, Yosef et al. (2016) Humanized Mouse Xenograft Models: Narrowing the Tumor-Microenvironment Gap. Cancer Res 76:6153-6158
Dionne, Lai Kuan; Wang, Xiao-Jing; Prekeris, Rytis (2015) Midbody: from cellular junk to regulator of cell polarity and cell fate. Curr Opin Cell Biol 35:51-8
Dionne, L K; Driver, E R; Wang, X J (2015) Head and Neck Cancer Stem Cells: From Identification to Tumor Immune Network. J Dent Res 94:1524-31