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Project
Spatial positioning in pancreatic tumors: mapping and deconstructing the underlying SLIT-ROBO pathway (FWOTM1141)
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest
cancers with a high metastatic capacity. Two transcriptomic subtypes
of PDAC are generally agreed upon: classical and basal-like tumors
of which the latter confer a worse prognosis. PDAC typically
comprise a large component of stromal cells that may direct the
spatial positioning of the tumor epithelial cells including metastatic
behavior. Using innovative technologies, the spatial distribution of
tumor cells and a selected set of stromal cells (cancer associated
fibroblasts (CAFs) and endothelial cells) will be mapped in patient
samples while discriminating classical and basal-like tumor markers.
Alongside, a signaling pathway is mapped that is known to guide cell
positioning in the nervous system and that is frequently altered in
PDAC, i.e. the SLIT ligand-ROBO receptor pathway. This SLITROBO positional system will further be deconstructed by assessing
its impact on the functional interaction of tumor cells with CAFs and
endothelial cells, underpinned by multicellular 3D co-cultures,
scRNAseq and 3D bioprinting, and with respect to tumor cell
migration, intravasation and vasculogenic mimicry. Key phenotypes
will be exemplified by applying state-of-the-art 3D microscopy in
human clinical samples. This project spatially profiles pancreatic
cancer (subtypes) and deconstructs an underlying spatial positioning
mechanism, which can offer novel leads for therapeutic intervention
cancers with a high metastatic capacity. Two transcriptomic subtypes
of PDAC are generally agreed upon: classical and basal-like tumors
of which the latter confer a worse prognosis. PDAC typically
comprise a large component of stromal cells that may direct the
spatial positioning of the tumor epithelial cells including metastatic
behavior. Using innovative technologies, the spatial distribution of
tumor cells and a selected set of stromal cells (cancer associated
fibroblasts (CAFs) and endothelial cells) will be mapped in patient
samples while discriminating classical and basal-like tumor markers.
Alongside, a signaling pathway is mapped that is known to guide cell
positioning in the nervous system and that is frequently altered in
PDAC, i.e. the SLIT ligand-ROBO receptor pathway. This SLITROBO positional system will further be deconstructed by assessing
its impact on the functional interaction of tumor cells with CAFs and
endothelial cells, underpinned by multicellular 3D co-cultures,
scRNAseq and 3D bioprinting, and with respect to tumor cell
migration, intravasation and vasculogenic mimicry. Key phenotypes
will be exemplified by applying state-of-the-art 3D microscopy in
human clinical samples. This project spatially profiles pancreatic
cancer (subtypes) and deconstructs an underlying spatial positioning
mechanism, which can offer novel leads for therapeutic intervention
Date:1 Nov 2022 → 22 Jan 2024
Keywords:Pancreatic cancer, tumor-stroma crosstalk, Spatial profiling
Disciplines:Cancer biology, Cancer therapy, Oncology not elsewhere classified