Regulation of colorectal cancer stem cell apoptosis and self-renewal by dependence receptors
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2024-04
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Melbourne Authors
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Clinical Pathology
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PhD thesis
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Open Access
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© 2024 Morgan Brisset
Abstract
The incidence of colorectal cancer (CRC) remains a significant global health concern, ranking among the most common types of cancer worldwide. Despite relatively good survival among patients with an early form of the disease, the prognosis for metastatic colorectal cancer (mCRC) remains grim, with drastically reduced survival rates once the disease has metastasized. This disparity in survival can be attributed to the limited efficacy of current treatment options, highlighting the urgent need for novel therapeutic approaches or strategies to enhance the effectiveness of existing treatments.
In this context, our project aimed to evaluate the implications of dependence receptors, specifically focusing on the UNC5B dependence receptor and its ligand Netrin-1, in modulating CRC and mCRC cells. Our study used a range of assays to characterize phenotypical characteristics, such as self-renewal using extreme limiting dilution assays, and transcriptomic assays such as RNA sequencing, and single-cell RNA sequencing on our patient-derived organoid model. Moreover, we assessed the therapeutical potential of targeting the UNC5B/Netrin-1 pathway using NP137, a neutralizing antibody for Netrin-1 currently undergoing clinical trials for solid tumours.
Our findings demonstrate that the UNC5B/Netrin-1 pathway plays a crucial role in modulating self-renewal and the induction of apoptosis in colorectal cancer stem cells. The inhibition of Netrin-1 by NP137 resulted in decreased self-renewal, increased cancer stem cell apoptosis and decrease of stemness-related genes in our patient-derived organoid cell lines.
Moreover, we demonstrate, in vivo, that targeting Netrin-1 with NP137 is an attractive and innovative therapeutic strategy that has the potential to enhance the efficacy of conventional chemotherapy in mCRC. Furthermore, our study reveals novel interactions between UNC5B and another dependence receptor, NOTCH3, which also contributes to the modulation of self-renewal in mCRC.
Overall, our research highlights the significance of dependence receptors in driving key cellular processes in CRC and mCRC, offering valuable insights into potential therapeutic targets and strategies. The identification of the UNC5B/Netrin-1 pathway implications in the regulation of self-renewal and apoptosis in colorectal cancer stem cells is providing solid foundations for future investigations and the development of treatments preventing chemoresistance and recurrence for metastatic colorectal cancer.
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Cancer stem cell, Apoptosis, Colorectal, Self-renewal, Metastasis, UNC5B, Netrin-1, Depedence Receptors