Laminin-associated integrins mediate Diffuse Intrinsic Pontine Glioma infiltration and therapy response within a neural assembloid model.

May 06, 2024

Experts: Sauradeep Sinha,Michelle S Huang,Georgios Mikos,Yudhishtar Bedi,Luis Soto,Sarah Lensch,Manish Ayushman,Lacramioara Bintu,Nidhi Bhutani,Sarah C Heilshorn,Fan Yang

Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive and fatal pediatric brain cancer. One pre-requisite for tumor cells to infiltrate is adhesion to extracellular matrix (ECM) components. However, it remains largely unknown which ECM proteins are critical in enabling DIPG adhesion and migration and which integrin receptors mediate these processes. Here, we identify laminin as a key ECM protein that supports robust DIPG cell adhesion and migration. To study DIPG infiltration, we developed a DIPG-neural assembloid model, which is composed of a DIPG spheroid fused to a human induced pluripotent stem cell-derived neural organoid. Using this assembloid model, we demonstrate that knockdown of laminin-associated integrins significantly impedes DIPG infiltration. Moreover, laminin-associated integrin knockdown improves DIPG response to radiation and HDAC inhibitor treatment within the DIPG-neural assembloids. These findings reveal the critical role of laminin-associated integrins in mediating DIPG progression and drug response. The results also provide evidence that disrupting integrin receptors may offer a novel therapeutic strategy to enhance DIPG treatment outcomes. Finally, these results establish DIPG-neural assembloid models as a powerful tool to study DIPG disease progression and enable drug discovery.
© 2024. The Author(s).

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ABOUT THE EXPERTS

Sauradeep Sinha,Michelle S Huang,Georgios Mikos,Yudhishtar Bedi,Luis Soto,Sarah Lensch,Manish Ayushman,Lacramioara Bintu,Nidhi Bhutani,Sarah C Heilshorn,Fan Yang

Sauradeep Sinha

Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.

Michelle S Huang

Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA.

Georgios Mikos

Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA.

Yudhishtar Bedi

Departments of Orthopaedic Surgery and Bioengineering, Stanford University, 240 Pasteur Dr., Biomedical Innovation Building 1254, Palo Alto, CA, 94305, USA.

Luis Soto

Department of Radiation Oncology, Stanford University, Stanford, CA, 94305, USA.

Sarah Lensch

Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.

Manish Ayushman

Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.

Lacramioara Bintu

Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.

Nidhi Bhutani

Departments of Orthopaedic Surgery and Bioengineering, Stanford University, 240 Pasteur Dr., Biomedical Innovation Building 1254, Palo Alto, CA, 94305, USA.

Sarah C Heilshorn

Department of Materials Science and Engineering, Stanford University, 476 Lomita Mall, McCullough Building, Room 246, Palo Alto, CA, 94305, USA. heilshorn@stanford.edu.

Fan Yang

Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. fanyang@stanford.edu.

Departments of Orthopaedic Surgery and Bioengineering, Stanford University, 240 Pasteur Dr., Biomedical Innovation Building 1254, Palo Alto, CA, 94305, USA. fanyang@stanford.edu.