Page 36 - SDIR5 Abstract book 21 12 2021.

IMAGING IN CANCER

Vessel co-option and resistance to therapy in glioblastoma

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Giorgio Seano
1 Institut Curie Research Center, Paris-Orsay, France
Centre national de la recherche scientifique (CNRS), France

Glioblastoma (GBM) is one of the deadliest types of human cancer. Despite a very aggressive treatment
regime – including resection of the tumor, radiation and chemotherapy – its recurrence rate is more than
90%. Recurrence is mostly caused by the regrowth of highly invasive and resistant cells spreading from the
tumor bulk, which are not removed by resection. To develop an effective therapeutic approach, we need
to better understand the underlying molecular mechanism of chemoradiation resistance and tumor
spreading in GBM.
GBM cells may use multiple strategies to spread in the surrounding brain tissue, one of them is vessel co-
option, i.e. the movement of tumor cells towards and along the pre-existing vasculature. By using intravital
microscopy we visualized and characterized the mechanisms driving vessel co-option in GBM. Interestingly,
these spreading and co-opting GBM cells may also acquire a resistant phenotype making them particularly
decisive during the GBM recurrence phase. This prompted us to deeply investigate the protective functions
of the perivascular niche environment.
Recently, using bulk and single cell RNA-Seq, in vitro and in vivo time-lapse imaging, organotypic cultures
and functional assays, we demonstrated that both chemoradiation and perivascular niche induce GBM
reprogramming towards a resistant subpopulation of GBM cells. Moreover, these resistant GBM cells are
more vessel co-opting allowing homing to the perivascular niche, that in turn induces further resistance to
therapy.
We are now investigating and targeting the upstream pathways responsible of reprogramming and vessel
co-option in order to reduce the intrinsic and extrinsic resistance to therapy typical of recurrent GBM cells.

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