Potential Therapeutic Target for Aggressive Colorectal Cancers

Colorectal cancer is the second leading cause of cancer-related deaths worldwide.

Although several molecular alterations associated with colorectal cancer have been identified, the mechanisms by which these changes drive cancer development remain poorly understood.

In a study published in the Journal of Clinical Investigation, researchers used mouse models and analyses of human colorectal cancer tissues to show that loss of the SOX9 gene accelerates tumor progression. The pathway influenced by SOX9 may also present a promising target for future therapies.

Previous studies by our lab and others have looked at the role of SOX9 in colorectal tumors. While some have shown SOX9 can contribute to colorectal cancer, others reported that reduced or absent SOX9 expression might be a contributing factor in tumor development.

Eric Fearon, Professor, Internal Medicine, University of Michigan

Eric Fearon, who also serves as Director of the Rogel Cancer Center, and his research team used mouse models to gain deeper insights into the role of SOX9.

They inactivated both the SOX9 and APC genes in colon tissues. APC is a tumor suppressor gene that is inactivated in approximately 80 % of colorectal cancer cases.

The researchers found that simultaneous inactivation of SOX9 and APC resulted in more aggressive tumors than inactivation of APC alone. Inactivating SOX9 by itself did not promote tumor growth.

Although our results do not indicate that SOX9 is a tumor suppressor gene in every patient’s colorectal cancer, our work establishes that inactivation of SOX9 contributes to tumor progression.

Eric Fearon, Professor, Internal Medicine, University of Michigan

The team also found that the invasive characteristics seen in colorectal cancers with low or absent SOX9 levels are driven by a process known as epithelial-mesenchymal transition.

During this transition, cells that typically remain anchored to the surface of the colon acquire the ability to migrate and invade surrounding tissues.

“These cells exhibit certain characteristics that help them metastasize to other sites, including the liver, lungs, and lymph nodes,” Fearon noted.

The findings from the mouse models were supported by clinical data from nearly 400 patients included in the TCGA Colon and Rectal Cancer cohort. The researchers found that 20 % of tumors had low or undetectable levels of SOX9.

Patients with reduced SOX9 expression had lower overall survival rates, further reinforcing the gene’s role as a tumor suppressor.

The team is now investigating how SOX9 interacts with APC to influence tumor development.

Our results highlight that there is more work to be done. Understanding why targeting both genes has such a markedly different effect compared to either gene alone can help us better understand why the subset of colon cancers lacking SOX9 has such poor prognosis.

Eric Fearon, Professor, Internal Medicine, University of Michigan