New frontiers in breast cancer research
Alison Allan, PhD, leads a team of researchers in studying metastasis, a leading cause of death and the greatest unsolved issue for cancer patients
By Ashley Rabinovitch
As Alison Allan, PhD, Chair, Anatomy and Cell Biology, can attest, there are few diseases more cunning or more devastating than cancer.
As a graduate student in molecular biology, she became fascinated by how cancer hijacks normal biological processes in the body. “I was driven forward by a desire to understand this phenomenon at a cellular level,” she said.
Near the end of her postdoctoral fellowship, her father lost a battle to pancreatic cancer only six months after diagnosis. In her grief, she resolved to continue along the path to become part of the global effort to develop better therapeutic options for cancer.
At the Schulich School of Medicine & Dentistry, Allan leads a team of basic and translational science researchers in studying the origin and behaviour of metastasis, the often-fatal spread of cancer from one part of the body to another.
About 50 per cent of their time is dedicated to developing and validating blood tests for tracking metastasis. Through studying tumour cells that circulate in the bloodstream, as well as DNA released from cancer cells, they are able to identify blood biomarkers to target with therapeutic drugs.
“We are in the middle of two Phase 3 clinical trials involving the use of our blood biomarker research to track patient response to a new radiation therapy against metastasis,” said Allan. “It’s amazing to be part of translational work that impacts patients almost immediately. Not every cancer researcher has the opportunity to witness the fruits of their labour in this way.”
“Metastasis continues to be the leading cause of death and greatest unsolved issue for cancer patients. Whenever we walk through patient waiting areas to get to our laboratory, we are reminded of the tremendous need for more research and more treatment. There is an urgency that never lets up.”
— Alison Allan, PhD
The other 50 per cent of the time, Allan and her team study breast cancer lung metastasis; the ability of cancer to spread between the two organs.
The lungs are one of the most common sites of breast cancer metastasis, particularly in patients with the aggressive triple-negative (TN) breast cancer subtype. Because of breast cancer’s ability to spread, it remains a leading cause of death in women.
Laying a Foundation
Five years ago, the Allan Lab began to investigate the features of different organ microenvironments, including the lung, which make them favourable to the spread and growth of breast cancer.
“We wanted to figure out how breast cancer cells and organ microenvironments talk to each other,” she said. “Specifically, we were interested in how breast cancer cells send signals to make the lung a favourable place for them to grow, and how we can modify the lung microenvironment to make it a hostile environment for these cells.”
Allan and her team observed a significant difference in how distinct molecular subtypes of breast cancer spread to the lungs. The luminal subtype of breast cancer, which has a better prognosis, did not modify the lung environment at all, they found. But TN breast cancer modified the lung environment in an aggressive way.
They began searching for reasons that might explain why certain types of breast cancer cells get into the lung through the bloodstream and grow into a tumour.
A few years ago, they identified one possible answer: extracellular vesicles (EVs) – particles that cells release to send messages to other parts of the body. “Think of EVs as little boxes that a courier will deliver to your house,” said Allan. “Inside the boxes are proteins and other molecules that tell cells to change.”
She and her team observed how EVs change the cells that line blood vessels to allow them to open up and let cancer cells through into the lung. EVs can also change the structure of the lung itself to make it more favourable to cancer cells.
In 2020, Allan’s research team published a paper that reported the difference between the two molecular subtypes of breast cancer and hinted at the role of EVs in breast cancer lung metastasis.
The Canadian Institutes of Health Research (CIHR) found this research so promising that it awarded Allan and her collaborators a Project Grant to fund their work from 2021 to 2026.
Digging Deeper
With CIHR funding in place, the research team began digging even deeper into the role of EVs in promoting breast cancer metastasis.
Using animal models, patient samples, 2D and 3D simulated lung environments and genomic profiling, they are laying the groundwork for identifying new targets for drugs that can prevent or reduce lung metastasis.
Currently, they are focusing most of their attention on microRNAs, a class of RNAs that turn genes on and off. If they can turn the right gene off, they can prevent it from making the EVs that promote breast cancer metastasis – and even prevent breast cancer from spreading to the lung in the first place.
The task before them is much like finding a needle in a haystack. There are thousands of genes to examine, and they are looking for those that are only expressed by triple negative cells, not normal cells.
In the meantime, they have already stumbled upon an existing drug that moves the ball further down the field. This drug was developed to inhibit a major protein involved in cancer growth, but it was never effective enough, so it was sitting on the shelf collecting dust.
“We were excited to find that this drug actually disrupts the cellular process by which cells make EVs,” said Allan.
She and her team have made great strides toward developing more therapeutic treatments for patients with breast cancer metastasis, and they are still picking up speed. For the next four years, their CIHR grant funding will allow them to make basic science discoveries with vast translational potential.
“Metastasis continues to be the leading cause of death and greatest unsolved issue for cancer patients,” said Allan. “Whenever we walk through patient waiting areas to get to our laboratory, we are reminded of the tremendous need for more research and more treatment. There is an urgency that never lets up.”
