This project is game-changing because it tackles GBM in a novel way using advanced genomics and CRISPR lineage tracing techniques. It focuses on understanding the role of hypoxia, a condition of low oxygen levels within the tumour, and its contribution to the cancer’s aggressiveness and resistance to therapy. The researchers believe that special cells in these low-oxygen areas can survive treatment and cause the cancer to return. By identifying these resistant cells, the project could lead to new targeted therapies that halt tumour progression.

By understanding the role of hypoxia and cancer stem cells in tumour resistance and recurrence, the project could lead to the development of new therapies that target these aspects of GBM. This could potentially improve treatment outcomes, reduce the likelihood of recurrence, and ultimately, increase survival rates for patients with this aggressive form of cancer.

This grant is focused on studying the role of hypoxia in GBM recurrence. The team will use spatial transcriptomics and CRISPR/Cas-9 single-cell RNA-seq to understand the genomic and cellular aspects of hypoxia in GBM. They plan to identify hypoxic areas in tumours using pimonidazole, a hypoxia marker, in patients with primary and recurrent GBM as part of their ongoing clinical study. They will compare primary and recurrent patient samples to identify treatment-related alterations in the hypoxic tumour microenvironment. This project aims to understand how hypoxia influences tumour development by studying the lineage of cancer stem cells in hypoxic niches using CRISPR-based in-vivo single-cell lineage tracing xenograft models. The Zadeh lab hypothesize that these cells transition between cellular states to escape therapy mediated by hypoxia. The resulting data will generate a novel atlas of progressive adult gliomas that combines both spatial transcriptomics data and high-quality single-cell clonal information. This will allow them to investigate the regional relationship between cancer cells inside and outside of hypoxic niches, and to track how the cells within these hypoxic niches develop through the use of high-quality phylogenetic trees. The ultimate goal of the research is to uncover key hypoxia-driven signalling pathways that contribute to treatment resistance and GBM recurrence.

The overarching aims of this grant includes:

Aim 1: Decoding the spatial transcriptome architecture of hypoxia in GBM upon recurrence.
Aim 2: Tracing hypoxia-associated tumour cell lineages with CRISPR/Cas-9 Cellular Barcoding.