ACTL6a ties metabolic reprogramming to cancer stem cell maintenance in oral cavity squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer mortality and treatment can cause significant functional impairments for survivors. Despite advances in treatment, survival rates have not meaningfully improved across many disease sites over the last several decades. Cancer metabolism is known to play important roles in tumor progression and treatment resistance, and HNSCC tumors undergo metabolic changes to increase energy production through glycolysis; however, the underlying mechanisms for this metabolic shift are poorly understood and targeting cancer metabolism remains elusive. The broad research goal of this proposal is to define how ACTL6A, a gene commonly amplified in HNSCC and a component of the SWI/SNF chromatin remodeling complex, contributes to metabolic reprogramming in HNSCC. Preliminary work shows that ACTL6A decreases mitochondrial potential of HNSCC cells and may be necessary for maintenance of a cancer stem cell like population of cells with low mitochondrial potential. These findings suggest ACTL6A expression levels may be important for regulating rates of ATP production from oxidative phosphorylation and glycolysis in cancer cells. To uncover how ACTL6A regulates cell metabolism, Aim 1 will quantify energy production in settings of low and high ACTL6A levels using HNSCC cells. An additional sub-aim will use an in vivo tumor model with a cancer drug targeting aerobic respiration along with a drug targeting SWI/SNF to establish a new strategy for treating HNSCC. Aim 2 will use CUT&RUN to define SWI/SNF distribution of a cell population with low mitochondrial activity and increased cancer stem cell gene expression whose population is nearly completely attenuated with ACTL6A knockdown. Together, these aims will establish the role of ACTL6A on cell metabolism, offer new combinations of therapies that may be effective against HNSCC, and open a novel area of research into regulation of cancer stem cell metabolism by SWI/SNF. Project Number: 1R03DE034489-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Andrey Finegersh | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $308,223 | Activity Code: R03 | Study Section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11232941