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A Reversible Metabolic Stress-Sensitive Regulation of Collapsin Response Mediator Protein 2A Orchestrates Cytoskeletal Remodeling and EMT, Increasing Metastatic Potential in Cancer
- Author / Creator
- Boukouris, Aristeidis
Cancer represents the second leading cause of death globally only after heart disease and is responsible for about 10 million deaths per year with a significant economic impact (WHO facts). Moreover, its prevalence is projected to increase over the following decades. Among all cancers, breast, lung and colorectal cancer represent the three most prevalent types of cancer. Intriguingly, it is estimated that 90% of all cancer morbidity and mortality is due to metastasis, i.e. the spread of cancer cells from the primary tissue of origin into surrounding structures and remote organs. Despite the several promising advances in cancer therapeutics, such as hormone therapy and immunotherapy, all available therapies are directed against the primary tumor, while no significant progress has been made regarding strategies to prevent metastasis. Therefore, a lot more work is needed in order to better understand the mechanisms and triggers of metastasis. The ability of cancer cells to metastasize is often preceded by a process called epithelial-to-mesenchymal transition (EMT), an extensive cellular rearrangement, which confers structural and molecular features to cells, enabling them to leave their original site and migrate to other tissues. It is thought that the signals to cancer cells for metastasis most often come from the surrounding stroma cells, mainly fibroblasts but also immune cells and vascular pericytes. Furthermore, the decision to metastasize, although beneficial for cancer cells in the long term, needs to be coupled with the metabolic state of cells and the fuel availability as EMT and metastasis are energy-intensive processes. Whether cancer cells also have “endogenous breaks” that need to be overcome for the process of metastasis to be fully activated and how these “breaks” relate to metabolic stress remains unknown. Identifying such cell-autonomous mechanisms of metastasis has the potential to create new important perspectives on cancer therapeutics, by preventing metastasis-related deaths.
Here we show that Collapsin Response Mediator Protein 2A (CRMP2A), a microtubule-associated protein (MAP) with implications in neuron development and neurodegenerative diseases, is reversibly induced in lung cancer cells in response to metabolic stress and regulates the ability of cells to undergo EMT/metastasis. Loss of CRMP2A results in increased invasion and metastasis in vitro and in vivo but also acquisition of a cancer stem cells phenotype, characterized by chemoresistance, increased tumor-initiating capacity and metabolic rearrangement towards increased nucleotide synthesis from glutamine, now all recognized as features of partial EMT and aggressive/metastatic tumors. We found that the ability of CRMP2A to regulate these important cell fate decisions relies on the remodeling of the cytoskeleton, which in turn regulates several EMT-related processes, such as transcription factor trafficking and ciliogenesis.
This is one of the very few reports that a single MAP, like CRMP2A is able to orchestrate a complex cytoskeletal, metabolic and EMT/stemness program in cancer cells. Our discovery may have important implications for therapeutic strategies aiming at halting metastasis.
- Graduation date
- Fall 2021
- Type of Item
- Doctor of Philosophy
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.