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Assessing TGF Beta1-Mediated ECM Remodeling in Metastatic Oral Squamous Cell Carcinoma

Award Number: F31DE032592
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Assessing TGF Beta1-Mediated ECM Remodeling in Metastatic Oral Squamous Cell Carcinoma - Abstract Oral squamous cell carcinoma (OSCC) patients have a dismal survival rate due to distant metastases that escape primary care. Transforming growth factor beta (TGFβ) 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 TGFβ 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 TGFβ 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 TGFβ 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 TGFβ-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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $45,294 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	3	10/29/2024	NON-COMPETING CONTINUATION	$45,294
														Subtotal = $45,294

Issue Date FY: 2024 ( Subtotal = $45,294 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	001	2	6/11/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	2	11/8/2023	NON-COMPETING CONTINUATION	$44,014
														Subtotal = $45,294

Issue Date FY: 2022 ( Subtotal = $43,072 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	1	9/20/2022	NEW	$43,072
														Subtotal = $43,072

Grand Total All Awards = $133,660

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Assessing TGF Beta1-Mediated ECM Remodeling in Metastatic Oral Squamous Cell Carcinoma

Award Number: F31DE032592

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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