Stard7 Protein Plays Dual, Context-Dependent Role in Intestinal Cancer

Researchers at the University of Liège have identified that the protein Stard7 plays a dual, context-dependent role in the development of intestinal cancers. This groundbreaking study, conducted using mouse models, revealed that Stard7 deficiency can either reduce or accelerate tumor growth depending on the specific type of cancer. This research also led to the creation of a new experimental mouse model that closely mimics human colorectal cancer.

Stard7 deficiency can either reduce or accelerate tumor growth depending on the specific type of cancer, highlighting a complex, context-dependent role in tumor development.

Background on Colorectal Cancer and Stard7

Colon cancer ranks as the third most frequently diagnosed cancer globally and is the second leading cause of cancer-related deaths. Despite advancements, the mechanisms driving this disease are not fully understood. To investigate these mechanisms, researchers at the GIGA Medical Chemistry Laboratory at ULiège focused on the Stard7 protein.

Stard7 was previously understood primarily as a transporter of specific lipids to mitochondria, which are essential for cellular energy production and for maintaining their own structure and function. The current study now recognizes Stard7 as being involved in mitochondrial metabolism and tumor progression within the intestine.

Stard7's Cellular Function and Deficiency Effects

To investigate Stard7's role, researchers developed mouse models where the gene responsible for producing Stard7 was selectively deactivated in intestinal cells. This targeted approach allowed for an examination of the consequences of Stard7 deficiency within the intestine.

Observations from Stard7-deficient intestinal cells included:

• Reduced mitochondrial activity, leading to decreased energy production.
• Increased generation of free radicals, which are unstable molecules capable of damaging cellular components and DNA.
• Cellular reorganization, involving alterations in fat composition.
• Activation of emergency programs driven by two key regulators:
  • mTORC1: A regulator that promotes cell growth and multiplication.
  • ATF4: A stress-triggered molecular switch that reprograms cells to produce serine, an amino acid often utilized by cancer cells for growth and resistance.

These observed cellular changes were found to create an environment conducive to tumor formation and progression.

Dual Impact on Cancer Development

The study revealed that Stard7's effects on cancer development vary depending on the specific conditions of the cancer:

In a model where cancer was induced by chronic intestinal inflammation (similar to inflammatory bowel diseases), Stard7 deficiency led to a reduction in tumor development. In this context, Stard7 appeared to facilitate the disease, and its absence offered protection to the intestine.

In a second model, designed to replicate the most common form of human colon cancer (triggered by a defect in the APC gene), Stard7 deficiency accelerated tumor development. Here, Stard7 functioned as a natural inhibitor, and its absence removed this protective mechanism.

Novel Animal Model and Implications

The second experimental configuration, combining an APC gene mutation with a lack of Stard7 in the intestine, resulted in a new mouse model. These mice rapidly developed numerous tumors in the distal colon, which is the segment most frequently affected in human colorectal cancer. This feature makes the model a relevant representation of the human disease.

This new model also exhibited a gut microbiota composition similar to that observed in human patients with colorectal cancer. This characteristic is expected to enable further investigation into the relationships between microbiota imbalance, mitochondrial dysfunction, and cancer development.

The findings suggest that Stard7 can function either as an inhibitor or an accelerator of cancer, depending on the mutational status of the tumors.

This duality emphasizes the necessity of understanding the specific characteristics of each tumor before considering treatment strategies, aligning with principles of personalized medicine. The study contributes significantly to the foundational knowledge required for developing improved treatments for colorectal cancer.