Unlocking MYC’s Secrets: New Treatment for Hepatocellular Carcinoma Using CRISPR Technology

MYC-driven hepatocellular carcinoma (HCC) involves the aberrant expression and activation of the MYC oncogene, playing a critical role in the pathogenesis, progression, and prognosis of HCC. MYC is a transcription factor that controls various cellular processes, including cell cycle progression, apoptosis, and metabolism. In the context of hepatocellular carcinoma, MYC overexpression can lead to uncontrolled cell proliferation, resistance to cell death, and metabolic reprogramming, all of which contribute to tumor development and growth. The pathogenesis of MYC-driven HCC involves multiple steps and factors. Genetic and epigenetic alterations leading to MYC overexpression or amplification are common in liver cancer. This aberrant MYC activation can result from various triggers, including viral hepatitis infections (especially hepatitis B and C), alcohol abuse, non-alcoholic fatty liver disease (NAFLD), and exposure to aflatoxins. Once MYC is overexpressed, it drives the transcription of numerous target genes involved in critical cellular functions, pushing liver cells toward a malignant phenotype.

MYC influences several molecular pathways critical for HCC development, MYC promotes the transition from the G1 phase to the S phase of the cell cycle, leading to increased cell proliferation. It also promotes and inhibits apoptosis, depending on the cellular context and the presence of other oncogenic signals. In HCC, MYC typically creates an environment that evades programmed cell death. Moreover, MYC reprograms cellular metabolism to support rapid tumor growth, enhancing processes like glycolysis and glutaminolysis, often referred to as the “Warburg effect.” Furthermore, MYC can promote the formation of new blood vessels to supply the growing tumor with nutrients and oxygen.  The involvement of MYC in HCC has significant clinical implications where the detection of MYC overexpression or amplification can help in diagnosing HCC and understanding its potential aggressiveness. Additionally, high levels of MYC are often associated with a poor prognosis, more aggressive disease, and a higher likelihood of recurrence after treatment. However, targeting MYC directly has been challenging due to its “undruggable” nature due to its lack of a defined enzymatic pocket for inhibitor binding and its involvement in essential cellular processes. However, strategies aimed at inhibiting MYC expression or its downstream effects are under investigation. These include the use of small molecule inhibitors, RNA interference, and strategies to disrupt MYC’s interaction with its transcriptional partners. Indeed, despite the clear role of MYC in HCC, targeting MYC in a therapeutic context remains a significant challenge. MYC’s involvement in normal cellular functions complicates the development of targeted therapies that can discriminate between its oncogenic and physiological roles. Future research is aimed at identifying more specific targets within the MYC pathway, improving the selectivity and efficacy of therapeutic interventions, and understanding the interaction of MYC with other oncogenes and tumor suppressor genes in HCC. Additionally, further insights into the molecular mechanisms of MYC-driven hepatocarcinogenesis will be crucial for developing novel diagnostic and therapeutic strategies.

A new study published in Nature Communications by Stanford University scientists and led by Dr. Anja Deutzmann, Dr. Delaney Sullivan, Dr. Renumathy Dhanasekaran, Dr. Wei Li, Dr. Xinyu Chen, Dr. Ling Tong, Dr. Wadie Mahauad-Fernandez, Dr. John Bell, Dr. Adriane Mosley, Dr. Angela Koehler, Dr. Yulin Li & Professor Dean Felsher, the authors conducted a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. The method allowed the researchers to identify genes essential for the survival of MYC-high cells, but not MYC-low cells, leading to the discovery of MYC synthetic lethal (MYC-SL) interactions.

The research team also found a range of novel MYC-SL interactions, as well as validating many previously identified ones. The new discovery is important in understanding the survival mechanisms of MYC-high HCC cells and opens new avenues for targeted therapy.  A significant revelation of this research is the identification of nucleocytoplasmic transport as a MYC-SL interaction. Nucleocytoplasmic transport, which is the process of moving molecules like RNA and proteins between the nucleus and cytoplasm, they showed it get upregulated in MYC-high murine HCC and linked to poor survival in HCC patients. Moreover, they demonstrated that inhibiting XPO1, a key player in nucleocytoplasmic transport, leads to marked tumor regression in MYC-transgenic HCC models and inhibits tumor growth in HCC patient-derived xenografts. This finding is particularly noteworthy as it suggests a novel therapeutic strategy for MYC-high HCC. The researchers hypothesized that MYC may regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis, indicating a broader impact of MYC on cell function and cancer development. The study’s findings have considerable clinical implications, especially in the  HCC management because the identification of MYC-SL interactions and the role of nucleocytoplasmic transport in MYC-high HCC, can identify new therapeutic targets. For instance, XPO1 inhibitors showed promise for treating MYC-high HCC, offering hope for a cancer subtype that has been notoriously difficult to treat. In conclusion, the new study led by Professor Dean Felsher and his team represents an important advancement in the fight against MYC-driven cancers, particularly HCC. By leveraging cutting-edge CRISPR/Cas9 technology and innovative approaches, the study not only deepens our understanding of MYC’s role in cancer but also paves the way for novel and potentially more effective treatments.