Thursday, May 2, 2024
5/2/2024
Abstract Oral squamous cell carcinoma (OSCC) patients have a dismal survival rate due to distant metastases that escape primary care. Transforming growth factor beta (TGFß) is a well-known driver of metastasis, modulator of immune cell activity, and regulator of extracellular matrix (ECM) genes. In breast cancer, a stiff ECM is generally attributed to excess type I collagen deposition and crosslinking that promotes cancer cell metastasis and cancer stem cell (CSC) expansion. In OSCC, a consensus has not been reached on whether a stiff or soft ECM increases metastatic potential and CSC expansion. The impact of OSCC ECM composition on immune cell trafficking is also unknown. Our laboratory has produced murine OSCC cell lines derived from Keratin15+ stem cells with Smad4 loss and KrasG12D mutation. Despite having the same genetic background, these cell lines have different metastatic ability, suggesting microenvironmental factors or cell intrinsic differences may mediate metastasis. RNAseq analysis revealed that metastatic OSCC cells have increased levels of laminins and laminin- binding integrins but downregulated type I collagen genes. Additionally, while OSCC cells cultured on stiff ECM demonstrate increased invasion, those cultured on a soft ECM display increased CSC characteristics. Treating metastatic OSCC cells with a TGFß inhibitor reduced migration and invasion. Comprehensive immune profiling using flow cytometry revealed that metastatic tumors have decreased numbers of CD8+ T infiltrating lymphocytes (TILs) compared to non-metastatic OSCC tumors. These CD8+ TILs are instrumental for a robust anti-tumor immune response and the success of immune checkpoint inhibitor (ICI) therapy. Identifying responders to ICI and TGFß inhibitors and sensitizing non-responders to these therapies persist as a major obstacle. Defining how OSCC cells interact with the ECM to promote their dissemination and enhancing current prognostic markers are both crucial to improve patient care and prolong survival. The goal of this proposal is to use unique murine models and human patient samples to define how ECM components and rigidity influence OSCC CSCs metastasis to improve the efficacy of emerging, targeted therapeutics to inhibit OSCC metastatic outgrowth. The hypothesis of this proposal is that elevated TGFß signaling in OSCC induces increased integrin expression and a laminin/collagen imbalance in the ECM, altering ECM stiffness and modulating OSCC metastasis, OSCC CSCs, CD8+ TIL motility and ICI responsiveness. I will 1) evaluate TGFß-dependency and function of laminins and associated integrins in OSCC metastasis; 2) determine how laminins contribute to ECM rigidity and subsequent impact on OSCC CSC characteristics and motility; and 3) assess if inhibiting laminin deposition enhances ICI. This study will provide insight into how enhanced laminin-binding integrin expression and laminin deposition facilitates OSCC metastasis, CSC characteristics, and CD8+ TIL exclusion. It will also identify predictive prognostic biomarkers for ICI and therapeutic targets for treating metastatic OSCC.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
