Building an artificial tumour in the lab

Fran Balkwill plans to build the world’s first artificial tumour

In 2000, a team of archaeologists in the ancient Egyptian city of Thebes uncovered the mummified remains of a young woman called Tabaketenmut. The big toe of her right foot was missing. In its place was a wood and leather contraption tied to the limb with string, which researchers believe to be the earliest example of a prosthetic body part.

This rudimentary device – developed more than 2,000 years ago to help a woman walk – is often cited as one of the first and most primitive examples of bioengineering, the use of artificial components to replace damaged or absent parts of the body.

Today the term has a much broader meaning and includes disciplines such as materials science, biology, mathematics, engineering and computing. And we’ve come an incredibly long way since – thanks to primitive bioengineering – Tabaketenmut walked the earth.

Just last month, we heard the astonishing news that scientists have been able to grow a functioning kidney in the lab. And researchers in the US have developed a high-tech ‘lung on a chip’ to help them study infections and other diseases.

Now Cancer Research UK scientist Professor Fran Balkwill is looking to make a similarly monumental step forward in cancer biology by bioengineering the first ever three-dimensional artificial tumour.

She hopes the work will underpin the development of new treatments that attack the interactions between cancer cells and healthy tissues that unwittingly support them, known as the microenvironment.

Rogue organ

Only a few years ago a project of this scope would have been unthinkable. Although both healthy cells and cancer cells have been routinely grown in the lab for decades, no one has yet come close to reconstructing accurately the complex ecosystem of cells that make up a tumour.

Cells growing in the lab

Professor Balkwill is based at Queen Mary University in London, and we’ve proudly supported much of her work over the years. When we spoke to her about her ambitious project, she explained that even at the earliest stages of development, cancers are more than just a group of cells with cancerous potential.

Instead, Professor Balkwill prefers to think of cancer as a ‘rogue organ’.

A normal organ – such as your liver or lungs – is made of several different cell types such as those that make blood vessels, immune cells that protect against infection, and fibroblast ‘builder’ cells that give the organ its structure.

But Professor Balkwill says that while many of these normal, healthy cells are present in cancer, they are coerced and corrupted by the malignant cells forcing them to grow and spread.”

For example, the blood vessel cells in a cancer don’t behave as they should, and instead form very abnormal and leaky vessels.

“On top of this, the immune cells can’t work properly because their normal ‘good’ functions have been suppressed by the cancerous cells”, she says, “and the fibroblasts grow too much and produce too many growth factors that help the cancer cells grow and expand.”

This dynamic mixture of normal cells and cancer cells is also known as the tumour microenviroment. Professor Balkwill has spent much of her distinguished career working to unlock the secrets of the microenvironment to find ways to tackle cancer.

CANBUILD: ovarian cancer

In particular, Professor Balkwill is determined to discover more about the role of the microenvironment in ovarian cancer.

This latest project – funded by the European Research Council – is shaped and complemented by her Cancer Research UK-supported work. Called CANBUILD, the five year project will bring together a diverse team of world experts to build a living ovarian tumour microenvironment.

Professor Balkwill hopes specifically to reveal more about the inner workings of a type of ovarian cancer called high-grade serous carcinoma (HGSC), the most common and lethal form of the disease.

Mouse model of ovarian cancer showing cancer cells in green, immune cells in pink and blood vessels in red

By the time women with ovarian cancer start to notice symptoms and are diagnosed with the disease, it has often already spread (metastasised) into the abdomen, which makes it much harder to treat successfully. Through her Cancer Research UK work, Professor Balkwill has already been using tissue samples from patients, as well as animal models, to study the complex microenvironment machinery that’s at work in these tumours. Her aim is to develop new treatments to target them.

For example, she’s working with our tech transfer arm Cancer Research Technology and pharmaceutical companies Affitech and AstraZeneca on ways to block a molecule called CCR4, which works on various immune cells in the tumour microenvironment.

Her team has also already developed a rudimentary three-dimensional model of ovarian cancer with three different cell types. Professor Balkwill now wants to take this research to the next level by building a whole living ovarian tumour in the lab – a complex three-dimensional human cancer in which the many different cell types of the microenvironment will communicate, evolve and grow.

Although it will be tiny in size – just a few millimeters across – the task is huge in ambition. And to meld successfully the many different cell types that make up a tumour she needs a successful meld of expertise from different scientific disciplines.

But recent developments in cancer stem cell biology, tissue engineering, mechanobiology and other fields mean that the timing is perfect to attempt such an elaborate project, according to Professor Balkwill.

Perfect timing

She has brought together a crack team of experts – many already supported by Cancer Research UK – who will each bring a unique set of skills to the venture:

• Dr James Brenton, a Cancer Research UK clinician scientist with expertise in ovarian cancer molecular biology and genetics, and cancer stem cells;

• Dr Michelle Lockley, a Cancer Research UK clinician scientist specialising in ovarian cancer;

• Professor Sussan Nourshargh, an expert in immunology, inflammation and state-of-the art microscope methods;

• Dr John Connelly, a tissue engineer with expertise in building artificial tissue scaffolds called ‘hydrogels’;

• Professor Ian MacKenzie, a cancer stem cell expert;

• Professor Martin Knight, an expert in mechanobiology and bioengineering;

• Dr Jeff Hubbell, an expert in biomaterials and tissue engineering.

Watch this space

Professor Balkwill describes the project as “blue sky research” that will stretch the skills and imagination of every member of her team, and could lead to a significant shift in how we study tumours in the lab. Her hope is that by more accurately reflecting how cancers behave in the human body, the model her team build will be a vital new weapon in the fight against the disease.

Her vision is to bring forward a “new approach to cancer treatment, where we attack both the supporting microenvironment and the cancer cells,” she says.

Just as the world of prosthetics has moved on dramatically from the days of Tabaketenmut’s crude artificial toe to the bespoke carbon fibre and robotic limbs of today, cancer treatment has improved dramatically. Powered by an ever-growing understanding the disease, we’re moving towards an era of precision medicines that are tailored more specifically to the genetic and molecular drivers of different tumours.

The ultimate aim of the CANBUILD project is to use the model as a testbed for targeted cancer treatments that exploit weaknesses in the interface between tumour cells and components of the microenvironment. And Professor Balkwill says her work is “only a small part of a vast national and international effort” that is uncovering so much new and exciting information about cancers. “This is already translating to new ways of detecting, preventing and treating cancer,” she says.

Alongside her CANBUILD funding, Professor Balkwill has also secured further funding from us to continue investigating ovarian cancer and how to treat it better. A key aim is that three years into the Cancer Research UK-funded programme they will be able to begin to use the CANBUILD model as another experimental tool.

If the work is successful, Professor Balkwill also hopes to develop sophisticated models of other cancers in the future.

Watch this space for further updates on the project.

Olly

• Read more about the tumour microenvironment