The Role of HA Remodeling and Mesenchymal Transitions in Glioblastoma

PROJECT SUMMARY
Glioblastoma (GBM) is a deadly disease with no effective therapy and is associated with one of the worst 5-year
survival rates of all human cancers. Current treatments, which include aggressive surgical care, radiotherapy,
and chemotherapy, are ineffective in part because of the highly adaptable nature of GBM, which facilitates
therapy evasion and a persistent evolution of disease. Recent work has revealed the crucial role of the tumor
microenvironment (TME) in regulating tumor cell plasticity, leading to efforts to create targeted TME-dependent
treatments to combat GBM progression. However, due to the complex nature of the TME and a limited
understanding of the relevant promoters of disease embedded within this milieu, progress in identifying promising
therapeutic targets remains challenging. Within in the TME, biophysical cues including matrix stiffness and
composition, have emerged as significant regulators of GBM cell aggressiveness. Focused investigations on the
biophysical mechanisms regulating GBM cell aggressiveness represent a novel approach to develop effective
GBM TME targeting therapies. The emergence of biophysical alterations in the TME remains poorly understood
with the process of TME tissue remodeling being an underappreciated aspect of GBM progression. Current
investigations indicate that alterations in hyaluronic acid (HA) secretion and digestion may affect tumor
progression through two major processes: 1) shape the biophysical characteristics of the evolving TME, and 2)
induce mesenchymal shifts that leads to increased dysregulations in ECM secretion, increased invasiveness,
and increased proliferation. This proposal seeks to clarify the contributions and mechanisms of ECM remodeling
by quantifying ECM alterations in tumor core and rim and by dissecting the mechanotransductive mechanisms
underlying HA-dependent tumorigenic control. To do this we will test the following hypotheses: 1) Core ECM
remodeling leads to elevated HA content that increases tissue stiffening due to increased HAS2 and HYAL2
activity in mesenchymal tumor regions, 2) Increased mechanical stiffness and HA presentation will synergistically
promote mesenchymal transitions that will lead to increased HASes and decreased HYALs, leading to
accumulation of HA with varying molecular weights and subsequent biophysical alterations, and 3) Increased
HA stiffness will increase CD44 mechanotransduction through CD44 clustering and ERM activity, leading to
upregulated pro-mesenchymal signaling via STAT3-NF-ΚB and LOX-Twist1 and LMW HA secretion. The
proposed studies will be the first to systematically dissect the ECM components of various patient matched
regions of GBM tumors and study their contributions to biophysical characteristics, mesenchymal transitions,
and HA-CD44 mechanotransduction.

Grant Number: 1R15CA274344-01A1
NIH Institute/Center: NIH
Principal Investigator: Joseph Chen