ABS 005: Investigating the Effects of Chr3p Deletion and VHL Haploinsufficiency in Lung Squamous Cell Carcinoma (LUSC) and Clear Cell Renal Cell Carcinoma (ccRCC)

Gayatri Bulsara ¹, Joanna N. Modi, PhD Candidate ² Alison M. Taylor, PhD ³

¹ Barnard College of Columbia University
² Pathobiology and Mechanisms of Disease, Herbert Irving Comprehensive Cancer Center
³ Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center

Van Wickle (2026) Volume 2, ABS005

Introduction: Aneuploidy, whole or chromosome arm copy number imbalance, is found in 90% of solid tumors. Despite its prevalence, the contribution of aneuploidy to tumor progression remains poorly understood. Chromosome 3p (Chr3p) deletion is a common event that occurs in 80% of lung squamous cell carcinoma (LUSC) and 90% of clear cell renal cell carcinomas (ccRCC). This study compares the effects of Chr3p deletion in lung epithelial cells and kidney epithelial cells. We focus on Von Hippel-Lindau (VHL), a tumor suppressor gene located on Chr3p. Deletion of Chr3p results in the loss of one copy of VHL, whose protein product targets Hypoxia Inducible Factor Subunit Alpha (HIF-α) for ubiquitin-mediated degradation. Loss of VHL function leads to HIF-α stabilization and the activation of genes involved in survival and proliferation. Previous research shows complete VHL loss induces tumor growth via HIF accumulation in ccRCC; however, outcomes of heterozygous VHL loss are not known. We hypothesize that VHL haploinsufficiency is sufficient to stabilize HIF-α and promote transcriptional tumor progression in LUSC.

Methods: To assess this, we first designed a CRISPR–based approach to induce whole and partial chr3p arm deletions in lung airway epithelial cells. To determine the direct effect of only VHL, CRISPRi and CRISPR-Cas9 were used to evaluate heterozygous VHL loss in lung and renal epithelial cells.

Results: HIF-α stabilization was observed in seven of eleven whole arm chr3p deleted clones in normoxia. In cells with partial arm deleted regions that included VHL, HIF-α accumulation was also found. Findings revealed HIF-α stabilization in lung cells but saw no HIF stabilization in renal cells, indicating tissue-specific variation.

Discussion: Ongoing research aims to evaluate HIF-α–dependent sensitization in the presence of HIF-α and VEGF inhibitors. This study holds significance as one of the first to examine VHL in LUSC, with findings that may inform therapeutic development in lung cancer.