Brain-Tumor-Microenvironment Study in Motion

Multiphoton live imaging allows to decipher immuno-vascular crosstalk over glioma tumor progression

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Glioblastoma is the most common and aggressive tumor of the central nervous system with poor patient survival and lack of effective therapies. Current therapeutic strategies are orientated toward neoadjuvant chemo-radiotherapy discovery, but dysmorphic tumor angiogenesis makes it challenging to deliver cytotoxic agents in an optimal way.

Intensive research into tumor-angiogenesis has been fueled by hopes to identify tumor-specific endothelial markers allowing vascular targeting to improve drug delivery or altering vessel formation. However, current challenges in non-invasive in vivo imaging and the chaotic nature of tumor vessels limit our ability to analyze vascular patterning in tumor-angiogenesis.

To overcome these limits, we developed a cranial window model allowing us to follow over time glioma grafts in mice. Applying inducible genetic strategies to direct endothelial cell-specific fluorescent-reporter expression (and/or macrophages), we have begun to investigate the dynamics of endothelial and stromal cells during tumor progression using a Leica DIVE multiphoton microscope.

Image: Live imaging pictures of GFP positive blood vessels growing in BFP positive tumor (left) and GFP positive macrophages invading the tumor via Tomato positive blood vessels (right).

In the present study, we show, in an in vivo longitudinal study, that the Slit-Robo pathway is critical for immunosuppressive myeloid cell accumulation in Glioblastoma. Genetic Slit2 depletion in tumor cells leads to cytotoxic myeloid cell accumulation, T-cell enrichment, and normalization of tumor blood vessels, resulting in increased sensitivity to chemotherapy. Administration of systemic Slit2 trap limits glioblastoma progression, demonstrating that the Slit-Robo pathway can be an innovative immunotherapeutic target for the treatment of glioblastoma.

Read the full article:

Geraldo LH, Xu Y, Jacob L, Pibouin-Fragner L, Rao R, Maïssa N, Verreault M, Lemaire N, Knosp C, Lesaffre C, Daubon T, Dejaegher J, Solie L, Rudewicz J, Viel T, Tavitian B, De Vleeschouwer S, Sanson M, Bikfalvi A, Idbaih A, Lu QR, Lima FR, Thomas JL, Eichmann A & Mathivet T.:

SLIT2/ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia

J Clin Invest, 2021

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