In the intricate biology of the human body, organs such as the breast, colon and lungs are lined with a defensive barrier known as the epithelium. At the heart of this barrier sits a remarkable protein called mucin-1 (MUC1). In a healthy body, MUC1 is like a sentinel.

It stands on the cell wall, draped in a complex âarmourâ of long chains of sugar molecules (carbohydrates), where it serves as a physical shield against bacteria, viruses and toxins. Crucially, it communicates with the immune system, telling the bodyâs natural defences when it is under threat.

But in the case of cancer, this guardian exchanges its sugar coat armour for shorter sugar chains and so turns into a traitor. It stops sending danger signals to the immune system and instead binds to the immune cells, creating an anti-inflammatory microÂenvironment that promotes tumours.

The team I lead at the Scientific Computing Research Unit at the University of Cape Town is home to computer modelling experts and experimental chemical biology research scientists. The molecular details of this MUC1 alteration, which contributes to the transformation of normal cells into tumour cells, were recently published in Nature Communications and provide a new look at exactly how this process happens.

By developing a novel âtest-tubeâ synthetic biology approach, we modelled and decoded the molecular assembly line reorganisation that allows cancer to âredecorateâ MUC1, turning it from a protective shield into a cloak of invisibility. We used our own computational chemistry algorithms to map the exact sugar coating positions that create a tumour-promoting environment.

Understanding the location and nature of the MUC1 sugars that prevent the immune system from detecting tumours provides the foundation for our laboratory and others in the field to develop cancer vaccines, biomarkers and therapeutics.

This South African-led discovery represents a major leap forward in our ability to decode one of cancerâs most effective survival strategies.

Malignant makeover

In a normal cell, the sugar molecules attached to MUC1 are long and complex. The process of attaching sugars is called glycosylation. In cancer cells, however, this process goes haywire. The sugar molecules are often cut short or altered, creating âaberrantâ structures like the Tn and sialyl-Tn (sTn) antigens. These are specific types of sugar-protein combinations that are tags for tumour cells.

These altered sugars do two dangerous things: they allow the tumour to evade detection by the immune system, and they actively trigger the process of turning a normal cell into a cancerous one.

Because MUC1 is found in so many different types of cancer, the US National Cancer Institute has ranked it as the most accessible target.

To stop the cascading effect of the MUC1 changes from normal to tumour cells, scientists first had to understand exactly how the âassembly lineâ breaks down.

Relocating the factory

Our research team set out to do something ambitious: recreate the transition from a healthy sugar coating to a cancerous one in a laboratory setting.

In normal cells, the enzymes that build these sugar chains (long molecules) live in a part of the cell called the Golgi apparatus, the cellâs âpackaging and delivery centreâ. We built an in vitro (test tube) model to simulate what happens when these conditions change. We discovered that in tumour cells, the enzymes responsible for starting the sugar chains are relocated to another part of the cell, the endoplasmic reticulum, essentially the cellâs âfactory floorâ.

This relocation changes everything. Here, the enzymes are no longer inhibited by the usual cellular checks and balances. They take over the sugar sites on the MUC1 protein, creating the foundation for the cancerous Tn antigen.

To take the study even further, we used quantum chemistry. We simulated the behaviour of atoms and molecules at the most fundamental level to find out where these changes are most likely to happen. We identified a specific location on the MUC1 protein, known as the T13 site, which cancer enzymes prefer. This specific interaction is what drives the massive increase in the sTn antigen seen in malignant tumours.

From lab to patient

Understanding the âhowâ and âwhereâ of these sugar changes is the first step towards stopping them. The research didnât stop at the test tube; the team is already looking at what this means for patients.

The next phase of the research, as detailed in a recent paper in Glycobiology, involves building a sophisticated âsystems biologyâ computational model. A model can connect the changes in the MUC1 sugar coating to the behaviour of immune cells. For example, scientists found that when these cancerous sugars interact with macrophages (a type of white blood cell), they trigger the release of specific signals that tell the tumour to grow and spread.

We are refining these details for various types of cancer. We are comparing common forms of breast cancer with more aggressive, currently untreatable types to see if the âsugar codeâ differs between them.

By using this accurate, atomic-level data to build computer models of the entire biological system, we hope to identify new drugs that can block these signals.

The goal is to move towards precision medicine: treatments that can strip away cancerâs sugar shield, allowing the patientâs own immune system to finally see and destroy the tumour. DM

First published by The Conversation â read the original article here.

This story first appeared in our weekly DM168 newspaper, available countrywide for R35.