An international research team has identified ‘born to be bad’ colorectal tumours in people with early stage cancer, which could help medical experts pinpoint and better treat aggressive tumours.
The team from Monash University, CRUK Beatson Institute in Glasgow and Queens University in Belfast found a feature of early-stage colorectal tumours in mice and humans, known as TGFβ signalling, that is active in tumour cells and is profoundly tumour-promoting.
In this group of patients, epithelial TGFβ signalling predicted how aggressive, treatment-resistant and lethal the cancer was/is.
Until now, such signalling pathways that identify the ‘bad’ tumours had only been found in late stage cancers. It is believed to be the first time they have been identified in early stage colorectal cancer.
Globally, 1.9 million colorectal cases were diagnosed in 2020, which is projected to grow to 2.2 million by 2030.
Published in Nature Communications, the study used molecular profiling to identify ‘born to be bad’ colorectal tumours that were likely to progress quickly due to the activation of TGFβ signalling in the tumour epithelium.
Joint first author Dr Dustin Flanagan, of the Monash Biomedicine Discovery Institute, said the findings could lead to improved and more personalised treatments for colorectal cancer patients who were likely to experience a relapse.
He said the TGFβ signalling effectively gave ‘born to be bad’ tumours the help they needed to become really nasty. Identifying this unique feature early could strongly predict whether they would become aggressive.
“This suggests tumour cells with ‘aggressive potential’ are pre-programmed from an early stage or ‘born to be bad’, rather than acquire these qualities over time,” Dr Flanagan said. “This challenges how we typically think about cancer progression, but also how and when to treat patients.
“We looked at patients diagnosed with early-stage (Stage I) colon cancer and noticed those who would go on to relapse had high levels of TGFβ signalling in the tumour epithelium.
“TGFβ is a cytokine that normally prevents cells from growing out of control. In other words, it’s a tumour suppressor, especially in early stages of the disease. But if the cancer mutates to become insensitive to TGFβ, then TGFβ ends up behaving as a tumour promoter.
“We showed that tumour cells with active TGFβ signalling stimulate additional growth-promoting pathways, exposing an Achilles heel which we can exploit with targeted therapies.
“Collectively, our findings have major implications for the prognosis and therapeutic management of colorectal cancer.”
Dr Flanagan said he and his colleagues were now collaborating with researchers in Italy and the UK to translate the findings using patient-derived organoid and xenograft (transplant) models.
“We are keen to test whether the same disease mechanisms (i.e. TGFβ signalling) used by primary colon tumours cells are also adopted by tumour cells that migrate to other sites in the body to establish metastatic disease,” he said.
“We will explore and identify other potential indicators of ‘born to be bad’ colorectal cancer that can be harnessed in a similar way to active TGFβ signalling.”
Read the full paper published in Nature Communications, titled Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features
DOI: doi.org/10.1038/s41467-022-35134-3
About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the Monash Biomedicine Discovery Institute (BDI) at Monash University brings together more than 120 internationally-renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.
