iSTARS ERA Chair João Guimarães Contributes to Study on the Effects of Low-Dose Radiation on Metastasis

A new study published in the International Journal of Molecular Sciences has investigated how low doses of ionizing radiation, that can affect tissues and organs near a tumour during cancer treatment, may influence the formation of pre-metastatic niches in the lungs. This process involves changes in the lung tissue that make it more receptive to disseminated breast cancer cells settling and growing there later on – forming metastasis.

The research was conducted by a multidisciplinary team from several Portuguese institutions, led by the angiogenesis research group headed by Dr. Susana Constantino Santos at University of Lisbon’s Cardiovascular Centre (CCUL@RISE), Lisbon Medical School. Among the contributors was iSTARS ERA Chair João Guimarães, who brought his expertise in computational biology and proteomics to the project. The study builds on the team’s previous work examining the biological effects of low-dose radiation and sought to model more clinically relevant conditions, specifically, the exposure of non-targeted organs to unintended radiation during radiotherapy.

“Over several years, we had published findings on the biological effects of low doses of ionizing radiation – such as those affecting healthy tissues during radiotherapy – and observed that, in an oncological context, these doses promote metastatic progression. However, in those studies, the entire body of the animal was exposed, which limited the translational relevance of the findings,” explains Dr. Susana Constantino Santos.  “We wanted to move closer to what might happen in patients, where only specific anatomical sites—especially potential pre-metastatic niches—are inadvertently exposed to low doses during treatment due to tumor location and radiation field geometry.”

The study, titled “Subtherapeutic Dose of Ionizing Radiation Reprograms the Pre-Metastatic Lung Niche, Accelerating Its Formation and Promoting Metastasis”, examines the biological effects of radiation doses too low to damage tissue directly. Using a mouse model of breast cancer, the researchers found that exposure to these low radiation levels could change the lung environment in ways that support the growth of metastasis.

Specifically, the study showed that low-dose radiation led to early changes in the lung, including the activation of immune responses and molecules linked to cancer spread. These changes were observed before any cancer cells were present in the lungs, suggesting that it may accelerate the development of a lung environment that supports future metastasis.

To better understand what was driving these changes, the research team analysed lung tissue at the molecular level. João Guimarães contributed to this part of the study, helping to examine how proteins and cell functions were affected by the radiation. The analysis showed that lung cells switched from their normal metabolism- oxidative phosphorylation and fatty acid metabolism- to a more stress-related, cancer-friendly type of metabolism – glycolysis and lipid accumulation.

“The use of proteomics, or other genomic technologies, in cancer biology have greatly improved our understanding of the molecular and cellular processes driving disease,” João Guimarães explains. “These tools help us characterise both tumours and their surrounding environments more deeply, allowing researchers to pose better research questions and more thoroughly dissect the mechanisms driving cancer development. On the other hand, this ability to collect large volumes of data brings an increased complexity in data analysis and biological data interpretation, requiring strong collaboration between experimentalists and computational biologists.”

That interdisciplinary collaboration, says Guimarães, was central to this Project: “This was a great example of the value of creating interdisciplinary teams to more effectively study complex diseases such as cancer. The constant interaction between experimentalists, clinicians and computational biologists during this project was a very rich learning experience and critical to make this study so successful.”

Santos echoes this sentiment, highlighting the importance of the collaborative approach across research and clinical teams:

“This study would not have been possible without the sustained collaboration with clinicians and researchers from diverse backgrounds. Our clinical partners, especially the Radiotherapy Department, led by Dr. Filomena Pina, played a critical role by supporting both the scientific questions and the infrastructure needed. The project also benefited immensely from the expertise of Dr. Karine Serre in immunology, Dr. Pedro Faísca in pathology, and from the contributions of proteomics and computational biology specialists. Above all, it was the dedication and resilience of researchers like Paula Oliveira and Inês Vala that allowed the project to move forward through its most challenging phases. The convergence of all these perspectives was truly the foundation of the study’s success.”

While the effects of radiation were most prominent at early stages, the authors note that subtherapeutic radiation seems to accelerate rather than fundamentally alter the process of pre-metastatic niche formation. One unexpected finding was that blocking the recruitment of neutrophils, immune cells previously linked to metastasis, did not stop cancer from spreading in irradiated mice.

As Guimarães notes: “We initially expected that preventing neutrophil accumulation would reduce metastasis. But even when we blocked that response, the mice still developed metastasis. This finding was surprising because it showed that low doses of radiation were promoting changes in the lung that supported metastasis independently of neutrophil accumulation.”

Santos elaborates: “This result really challenged our assumptions. It was only through proteomic analysis that we uncovered a broader network of radiation-induced changes—metabolic reprogramming, extracellular matrix remodeling, and altered cell adhesion— that seem to drive the accelerated development of metastases at later stages. These findings shifted our understanding and opened new avenues for further exploration.

Looking ahead, the team believes these insights could help guide the optimisation of radiotherapy protocols.

“Clinicians and dosimetrists should be aware of the potential unintended consequences of exposing specific anatomical regions to low-dose radiation,” says Santos. “Recognising and protecting these areas during treatment planning may become an important part of personalised cancer care.”

Guimarães adds:  “Of course, the benefits of radiotherapy are well established, but we hope this study raises awareness about the need to combine or improve current therapies to minimize the risks of radiotherapy in the treatment of cancer patients.”

By identifying specific biological pathways involved in this process, the research provides a basis for further studies aimed at minimizing unintended side effects of radiation in cancer patient treatment.

Full article available at: https://doi.org/10.3390/ijms26136145