CIPF leads a study on the mechanisms that facilitate metastasis that could serve as therapy in colorectal cancer.

The CIPF Advances a New Approach to Tackling Colorectal Cancer

• Researchers are investigating new therapeutic targets to specifically block an activity of actin, a protein abundant in cells.

• This study, led by researcher María Ángeles Juanes, has been published in iScience, part of the Cell Press group.

València (22.05.2024). A study led by María Ángeles Juanes, a researcher at the Príncipe Felipe Research Center (CIPF), focuses on understanding the mechanisms that facilitate cell invasion, a fundamental aspect in advancing knowledge about cancer.
Dr. Juanes, an Excellence Researcher under the Plan GenT of the Generalitat Valenciana, has recently published this significant discovery in iScience. The findings could be used as a targeted therapy in the early stages of colorectal cancer.

The metastatic process begins when cancer cells acquire invasive properties, which involve structural changes promoted by the actin cytoskeleton—a field in which Dr. Juanes and her team are experts. Actin is a highly abundant protein in cells.
Since most cancer-related deaths are caused by metastasis, understanding and preventing this process before it occurs is a crucial goal for the CIPF team.

The invasion of cancer cells into surrounding tissues is often the first step in metastasis. To invade tissues, cells must migrate, and actin plays a fundamental role in this process.

In this context, actin forms filaments that push the inner membrane of the cell, generating extensions that allow it to move in a specific direction. Cell movement is essential for tissue repair and embryonic development, among other functions. However, abnormal migration can lead to invasion and, consequently, metastasis.

Some drugs that globally affect actin have had very limited therapeutic use because actin regulates many fundamental cellular functions beyond migration, such as cell division, organelle transport, vesicle trafficking, and metabolic activities.
As a result, blocking all actin within a cell would cause severe side effects or even lead to cell death.

The CIPF research team has studied the molecular mechanisms involved in actin dynamics to develop strategies that selectively block the formation of invasive actin networks or extensions, preventing the spread of cancer cells to other parts of the body.

Targeting Actin-Driven Invasion

Dr. María Ángeles Juanes’ laboratory investigates the specific mechanisms that facilitate cell migration and invasion. Using the Adenomatous polyposis coli (APC) gene as a model, Dr. Juanes has demonstrated that APC facilitates the assembly of actin filaments in cells—a function that is essential for proper cell adhesion and migration.

Colorectal cancer is the third leading cause of cancer-related death worldwide, and 85% of cases are associated with APC gene mutations.

“We have studied the mechanisms by which Adenomatous polyposis coli promotes actin filament formation in the context of cell invasion. Cell movement is vital, but excessive movement—or even normal-speed movement in the wrong direction—can result in invasion and metastasis. Cells may lose their way, arrive too quickly at unintended locations, and accumulate in tissues where they could block blood flow, nutrient delivery, or other essential cellular functions,” explained the Valencian researcher.

Furthermore, other well-known proteins, called formins and the Arp2/3 complex, also assemble actin filaments. “We have studied the role of each protein separately and in combination,” Juanes added.

The discoveries made by María Ángeles Juanes’ team are crucial for designing and developing small molecules that specifically block the formation of APC-dependent actin filaments—invasive structures that promote cancer progression. The ultimate goal is to prevent cancer development.

The Value of Basic Cancer Research

For this project, the CIPF team used genetic treatments—specifically a mutant model they have been working with for years—along with pharmacological treatments and innovative microscopy techniques applied to preclinical models of colorectal cancer.

Currently, the group is using similar techniques and models, as well as artificial intelligence algorithms to design new molecules (or compounds) that could be used as anti-invasive therapies.

This project is a clear example of how basic research allows us to understand the underlying mechanisms of human diseases. Molecular knowledge is essential for gaining a detailed understanding of complex cellular processes and for developing more effective cancer therapies—not only for colorectal cancer but for other types as well.

Link to the article: https://doi.org/10.1016/j.isci.2024.109687