BLRD Research Career Scientist Award Application

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The overarching objective of my research program is to identify markers for prognosis and therapeutic interventions for squamous cell carcinomas (SCCs), hence improving health outcomes for veterans. SCCs arise from stratified epithelia; the most relevant organ sites in veterans are the skin and oral cavity where high exposure to UV irradiation and tobacco carcinogens make the total and high-risk SCCs significantly higher than in the civilian population. The worst outcome of SCC is death caused by distant metastasis. Skin SCC deaths exceed melanoma deaths and SCC deaths in the head and neck are 3-4 times higher than skin SCC deaths. The long-term goal of my VA research program is to identify markers for prognosis and therapeutic interventions for SCCs, hence improving health outcomes for veterans. Since being funded in 2016 by a VA Merit Award, my laboratory has been studying mechanisms related to SCC progression and therapeutic interventions. These studies continuously translate into clinical diagnosis and therapeutic interventions directly impacting veterans’ healthcare outcomes. My laboratory pioneered inducible and epithelial-specific genetic engineered mouse models (GEMMs) that develop SCCs and metastasis in the natural microenvironment and immune system. These models provide unique resources for cross-species comparisons with human SCCs and performing experimental therapeutics, including immunotherapy, in my past and ongoing Merit Award research. SCCs are often indolent for decades. In the previous funding period, we focused on studying how SCCs break indolence to become aggressive and metastatic cancers. We found that the properties of a subset of cancer stem cells (CSCs) are responsible for breaking indolence through both clonogenicity and invasion. We found that “heterozygous loss” of SMAD4, a tumor suppressor, in 30-50% of head and neck SCCs in humans, is a result of significant inter- and intra-tumor heterogeneity at the single cell level, and that SMAD4 mutant cells have a growth/survival advantage allowing them to take over the entire population of tumor cells. These findings provide critical prognostic value for examining SMAD4 genomic status at the single cell level. Further, SMAD4- deficient SCC cells have “Brca-like” defects in DNA damage repair that are susceptible to cancer therapies that target DNA repair pathways. This finding provides an important link for a therapeutic marker and strategy, and instigated an investigator-initiated clinical trial to treat locally advanced head and neck SCC with radiotherapy (RT) in combination with Olaparib, which included recruiting VA patients. In tumor stroma, we found that SMAD4 genomic loss triggers overproduction of TGFβ1, an immune suppressor and promoter for cancer progression. In addition, cancer associated fibroblasts (CAFs) secret more TGFβ than cancer cells and provide a CSC niche at the distant metastasis site for CSC clonal expansion. We also found that tumor-associated macrophages (TAMs) contribute to breaking indolence by CSC expansion through anti- apoptosis and angiogenesis. Further, SMAD4 mutant SCC cells have advantages in clonogenicity and immune evasion but paradoxically produce more DNA damage-associated neoantigens susceptible to anti-tumor immunity, pointing to therapeutic intervention strategies. We identified that SCCs with Smad4 loss changed the TME to be TGFβ and PD-L1-rich in myeloid cells, which are highly susceptible to immune eradication by dual TGFβ/PD-L1 targeting. These findings are ready to be translated to a clinical trial of radiotherapy in combination with dual TGFβ/PD-L1 targeting in advanced head and neck SCC patients including VA patient accrual, thus bringing therapeutic intervention in real time to our veterans. Ongoing research areas include: 1) Assess intrinsic properties of SCC cells that contribute to self-autonomous expansion and metastasis. 2) Identify SCC metastatic niche established by stromal cells. 3) Identify mechanisms of SCC immune evasion and immunotherapy interventions for SCCs.