Characterizing the role of SRCAP in Epidermal Homeostasis and Squamous Cell Carcinoma - Project Summary/Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy, disfiguring one million
and killing 15,000 people per year in the United States. Since the molecular drivers of cSCC are incompletely
characterized, few treatment options exist for cases which surgery does not cure. This research plan is focused
on characterizing a chromatin remodeler that is highly mutated in non-melanoma skin cancers, but is currently
understudied in human tissue. The first aim will define the wild-type regulatory mechanism using genomics
approaches in primary human keratinocytes. A mutational hotspot was also identified in epithelial tumors using
existing cancer genomics data. Genomic and proteomic approaches will determine the molecular mechanism
governing how this hotspot mutation induces gene dysregulation. Preliminary RNA-sequencing revealed that
knockdown of the catalytic subunit dysregulated DNA repair and the composition of the extracellular matrix
(ECM), pathways implicated in cancer progression. Therefore, aim two will functionally characterize how
mutation influences cancer progression. The ECM composition will be examined by western blot while the
resulting changes to epidermal adhesion will be probed by immunostaining and microscopy. The ECM informs
cellular behaviors such as proliferation and migration, which will also be investigated. These results will reveal
any pro-cancerous changes to both the epidermal niche and epidermal progenitors. Finally, an established,
inducible cSCC xenograft model will be used to determine whether the hotspot mutation accelerates cancer
progression. Altogether our results will define the regulatory mechanism of an under-characterized chromatin
remodeler in epidermal homeostasis and carcinogenesis. These results will provide functional evidence
informing whether SRCAP represents a useful cSCC biomarker or a worthwhile future therapeutic target.
The proposed research will be completed in the Interdisciplinary Biological Sciences graduate program at
Northwestern University under the supervision of the sponsor, Dr. Xiaomin Bao, and the co-sponsor, Dr.
Kathleen Green, who are experts in epidermal biology with skillsets that support the proposed experiments.
Training will take advantage of workshops, seminars, and core facilities available on both the Evanston and
Chicago campuses. This research and training plan is designed to develop the applicant's scientific technical,
analysis, communication, and mentorship skills and independence necessary to successfully transition to
postdoctoral training and ultimately a career conducting biomedical research.
