Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Xiaolu Yang

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal form of primary brain cancer. Despite the current standard-of-care therapies, glioblastoma remains universally fatal with median survival of less than 2 years. Cancer stem/propagating cells (CSCs) are functionally defined by the enriched capacity to propagate tumors in vivo, as well as self-renewal and differentiation potentials to establish cellular hierarchy and heterogeneity. Numerous studies support that GBMs harbor a subpopulation of highly tumorigenic, stem-like cells (GSCs), and that GSCs are responsible for glioma propagation and resistance to conventional therapy. However, how GSCs maintain their stemness remains unclear. Here, we show that during the differentiation of glioma stem cells, the activity of chaperone-mediated autophagy (CMA), a form of autophagy that selectively targets cytoplasmic proteins for lysosomal degradation, is significantly upregulated. Moreover, increasing of CMA activity through either forced expression of LAMP2A or the CMA activator QX77 leads to GSCs differentiation as well as reduced self-renewal capacity, whereas knockdown of LAMP2A has the opposite effects. Mechanistically, CMA targets cellular inhibitor of PP2A (CIP2A), which is responsible for MYC stabilization, for lysosomal degradation. MYC and MYC-regulated de novo purine synthesis pathway plays a vital role in glioma stem cells maintenance. These findings suggest that CMA regulates the stemness of GSCs and that combined treatment of chemotherapy drugs and CMA activators that force the differentiation of GSCs may represent a promising therapeutic strategy.

Embargoed

Available to all on Friday, January 31, 2025

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS