# Stromal Regulation of Basal Cell Carcinoma Formation

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $329,562

## Abstract

Project Summary
Advanced basal cell carcinomas are caused by the inappropriate activation of the hedgehog
pathway, and rapidly acquire resistance to Smoothened inhibitors. Previous work by ARO46786
developed a bioinformatic pipeline with cell line and animal model validation to identify tumor
mutations in canonical pathway members such as Smoothened, increased expression of the Gli
kinase atypical protein kinase C, and tumor pathway switching to another epidermal cancer,
squamous cell carcinoma. Despite these findings, many of the resistant BCCs lacked identified
resistance mechanisms, suggesting the existence of additional resistance pathways. Using multi-
dimensional genomics approaches and a new murine model of resistant BCCs, we have
uncovered two additional novel resistance pathways whose biology will be explored in the next
funding cycle: 1) Hh pathway repressor mutations of the primary cilium, where the normal
mechanisms that the centrosome-based organelle uses to dampen Gli activity are lost. We will
study one of the most commonly mutated genes protocadherin15 by dissecting how
protocadherin15 regulates hedgehog signaling and ciliogenesis and determining the fitness of
protocadherin15 mutations in vivo; 2) Cytoskeletal-associated transcription, where signals from
the local environment enhance Gli activity through the activation of the serum response factor /
myocardin-related transcription factor complex that binds to Gli. We will dissect the functional
interaction between Gli and the serum response factor / myocardin-related transcription factor
complex and elucidate the upstream environmental activators that confer resistance. Completion
of these aims will fill in major gaps in our understanding of tumor evolution and help develop new
therapeutics for advanced BCCs and other cancers.

## Key facts

- **NIH application ID:** 9906159
- **Project number:** 5R01AR046786-19
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Anthony E Oro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,562
- **Award type:** 5
- **Project period:** 2001-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906159

## Citation

> US National Institutes of Health, RePORTER application 9906159, Stromal Regulation of Basal Cell Carcinoma Formation (5R01AR046786-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9906159. Licensed CC0.

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