Date of Award

12-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Integrated Program in Biomedical Sciences

Track

Cancer and Developmental Biology

Research Advisor

John D. Schuetz, PhD

Committee

Suzanne J. Baker, PhD Mondira Kundu, PhD Yi Lu, PhD Joseph T. Opferman, PhD

Keywords

ABCA13, Hedgehog pathway, Cholesterol, SHH-MB

Abstract

Our current understanding of vertebrate hedgehog (Hh) pathway regulators is still evolving. As Hh signaling governs cerebellar development and constitutive activation drives SHH-Medulloblastoma (SHH-MB) formation, gaining a more thorough grasp of Hh pathway signaling can lead to advancements in SHH-MB therapy. The inhibition of Smoothened (SMO) by Patched (PTCH) is thought to be through PTCH restricting SMO access to cholesterol. Therefore, modulators of cholesterol homeostasis represent a promising but underexplored group of Hh pathway regulators. The ATP-binding cassette transporter A (ABCA) subfamily of proteins are known modulators of lipid homeostasis, however, to date, there has been no link between ABCA subfamily and Hh pathway regulation. Through siRNA-mediated knockdown of Abca genes and a GLI luciferase reporter assay, we identified here first the orphan ABC transporter ABCA13 as a positive regulator of SHH signaling. We used NIH-3T3 cells, a cell line frequently used to model Hh pathway function, to determine ABCA13’s role in Hh pathway regulation. Genetic ablation of Abca13 significantly decreased pathway output downstream of Hh pathway activation via ligand stimulation, direct SMO agonism, and oncogenic SMO activation. Knockdown of Suppressor of fused (Sufu) rescued pathway activity, positioning ABCA13 upstream of SUFU and at the level of SMO. We hypothesized that ABCA13 was mechanistically regulating the Hh pathway through alteration of cholesterol homeostasis. Indeed, Abca13 loss decreased cholesterol efflux and reduced cholesterol accumulation at the primary cilium under SHH-activated conditions, yet Abca13-deficient cells had increased total cellular and esterified cholesterol content, suggesting an uncoupling of overall cholesterol abundance from proper cholesterol localization. The addition of exogenous water-soluble cholesterol, and not known pathway-activating oxysterols, restored Hh signaling. Consistent with in vitro findings, in a clinically relevant SmoM2-driven SHH-MB mouse model, loss of Abca13 increased survival, reduced tumor burden, and downregulated Hh pathway and target gene expression. These findings identify ABCA13 as an unrecognized sterol-trafficking determinant and mechanistically distinct regulator of the Hh pathway that sustains SMO signaling and show that it promotes SHH-MB progression.

ORCID

https://orcid.org/0009-0002-6723-7611

DOI

10.21007/etd.cghs.2026.0707

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Available for download on Thursday, September 28, 2028

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