Oral squamous cell carcinomas (OSCCs) are proposed to contain a subset of tumor cells whose stem cell-like molecular and functional properties are required to sustain tumor growth. In a hierarchical model, these cancer stem cells (CSCs) are the only cells with unlimited self-renewal capacity and thus may be targeted in isolation to achieve tumor control. However, there is increasing evidence that some non-CSCs have the phenotypic plasticity to return to the CSC pool and thus retain therapeutic relevance. Accurately defining non-CSCs that can support an oral CSC pool together with mechanisms that drive these cells toward a CSC state would establish novel paradigm for OSCC treatment. Our preliminary work has isolated OSCC cells residing in a G0- like cell state previously found to have high growth potential, innate drug resistance, and low levels of Akt. Despite lacking molecular markers of CSCs, these cells displayed high tumorigenicity in vivo. Our working hypothesis is that the functional properties of G0-like cells reflect their ability to transition t a CSC state. We have also identified a putative CSC population in OSCCs, based on high expression JARID1B, a histone demethylase known to maintain other malignant and normal stem cell phenotypes. JARID1Bhigh cells exhibit both functional and molecular stem cell traits and are further distinguished from the G0-like subset by hyper- activation of the PI3K-Akt signaling pathway. To explain these findings, our overall hypothesis is that reactivation of the PI3K-Akt pathway in G0-like cells supports their return to the CSC pool by driving their transition to a JARID1Bhigh state. To test this hypothesis, we will first test the roles of the JARID1Bhigh and G0- like subsets in OSCC growth using conventional CSC molecular and functional criteria (aim 1). We will specifically test whether JARID1Bhigh cells have independent CSC functions, while tumor formation by G0-like cells may depend upon the JARID1Bhigh fraction. Additional studies will elucidate how PI3K-Akt signals regulate transitions among CSCs, G0-like cells, and the broader non-CSC pool (aim 2). Here we will test whether modulation of the PI3K-Akt pathway affects the sizes of the G0-like and JARID1Bhigh pools and/or the ability of non-CSCs to transition toward a JARID1Bhigh CSC state. Together these studies would provide valuable insight into the hierarchical organization and plasticity of non-CSC and CSC subsets within OSCCs.

Public Health Relevance

Oral squamous cell carcinomas (OSCCs), a major public health issue in the US, account for approximately 36,000 annual cases and 8000 deaths as well as severe treatment-related disabilities in many survivors. OSCCs putatively contain small subsets of cancer stem cells (CSCs) that are required to sustain tumor growth and contribute to drug resistance and tumor recurrence. The current proposal will use innovative and collaborative approaches to explore the cell types and mechanisms that maintain the CSC pool in OSCCs, providing a foundation for the development of novel, less toxic therapies to achieve durable CSC eradication and lasting tumor control in OSCC patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DE024685-02
Application #
8867033
Study Section
NIDR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2014-07-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Facompre, Nicole D; Harmeyer, Kayla M; Sahu, Varun et al. (2018) Targeting JARID1B's demethylase activity blocks a subset of its functions in oral cancer. Oncotarget 9:8985-8998
Facompre, Nicole D; Harmeyer, Kayla H; Basu, Devraj (2017) Regulation of oncogenic PI3-kinase signaling by JARID1B. Oncotarget 8:7218-7219
Facompre, Nicole D; Sahu, Varun; Montone, Kathleen T et al. (2017) Barriers to generating PDX models of HPV-related head and neck cancer. Laryngoscope 127:2777-2783
Harmeyer, Kayla M; Facompre, Nicole D; Herlyn, Meenhard et al. (2017) JARID1 Histone Demethylases: Emerging Targets in Cancer. Trends Cancer 3:713-725
Facompre, Nicole D; Harmeyer, Kayla M; Sole, Xavier et al. (2016) JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers. Cancer Res 76:5538-49
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