Julie Rytlewski

Interdisciplinary Training

Julie Rytlewski

"Understanding vascular niche modulation of squamous cell carcinoma to uncover new anti-tumor targets"

Head and neck squamous cell carcinoma is one of the most common forms of cancer worldwide
and has a 5-year survival rate of only 40-50%. This survival rate has stagnated with current
therapies, and new strategies are needed that intercept a multitude of survival pathways to
which tumors are addicted. The vasculature has been an increasingly central target for next-
generation anti-tumor therapies. However, its regulatory role in tumor pathogenesis has been
previously underestimated: new studies have shown direct links between vascular dysfunction
and local oncogenic transformation. We propose a new vascular-centric mouse model to
investigate the relationship between genetic abnormalities in the endothelium and squamous
cell carcinoma pathogenesis. Pilot studies have already confirmed our ability to successfully
deliver lentiviral gene vectors to the endothelium and pericytic cell niche via in utero injection
into the embryonic heart and placental blood supply. Candidate genes for overexpression will
be preselected based on transcriptome sequencing of freshly isolated tumor endothelial cells
from human squamous cell carcinomas. Genes significantly overexpressed in the tumor
endothelium will be used to generate a pooled lentiviral library for cDNA overexpression in a
functional in vivo screen. Pooled lentivirus will then be injected in utero for transduction of the
endothelium in K14-Cre/PIK3CA and K14-Cre/PIK3CA/TP53 mouse models of sensitized and
oncogenic squamous cell carcinoma, respectively. Mice will be monitored for rate of tumor
initiation, growth, and metastasis. Tumors will be individually isolated and sequenced to
identify the transduced cDNA underlying the oncogenic event, identifying potential endothelial
genes for therapeutic targeting.