Breast cancer patients, as well as patients with many other types of cancer, almost never die from the primary tumor, but from distant metastases –secondary malignant growths at a distance from a primary site of cancer – that have developed sometimes after years, in essential organs such as the lungs and brain.

Advanced metastatic cancers are mostly incurable, and available therapies generally prolong life to a limited extent. Thus, identifying the processes that lead to the spread and reception of metastases at an early stage may save millions of lives. 

A new study from Tel Aviv University (TAU) discovered changes in healthy lung tissue which indicate preparation o receive metastases. The changes were identified in the area known as “the micro-environment” of the tumor, and specifically in connective tissue known as fibroblasts. Researchers claim that these changes in the tissues are an early sign for the possible development of disseminated cancerous cells to other parts of the body. The researchers said that understanding the metastatic process and its diagnosis at such an early stage could lead to life-saving, preventive treatment. 

The study conducted was led by Prof. Neta Erez, chairman of the pathology department at TAU’s Sackler Faculty of Medicine and the research team of her laboratory, Dr. Ophir Shani and Dr. Yael Raz, as well as additional researchers from TAU, Tel Aviv Sourasky Medical Center, Sheba Medical Center at Tel Hashomer and the Weizmann Institute of Science in Rehovot. 

The paper was published in the journal eLife under the title “Evolution of fibroblasts in the lung metastatic microenvironment is driven by stage-specific transcriptional plasticity.” 

Metastases may appear even in patients who have undergone all the treatments offered, including surgical removal of the primary tumor, subsequent chemotherapy, and radiation meant to destroy any residual tumor. Methods used for follow-up today locate metastases only when they are quite large – when the disease is at an advanced stage and oncologists are unable to cure the disease. 

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For this reason, Erez’s research group has been investigating the “black box” – the time period between apparent recovery and the appearance of metastases – to understand the metastatic process and identify it in its early stages. Their research in the last years has revealed that designated tissues in organs where the metastases are set to arrive “prepare the area” for reception and produce a hospitable environment for them –a long time before the appearance of the metastases themselves. 

In the present study, the research team searched for signs of these changes that may be used in the future to identify the start of the process. The researchers focused on connective tissue cells known as fibroblasts, which are found in the lungs among other places. Lungs are one of the most common sites of breast cancer metastasis. Various immune cell populations were shown to be functionally important in facilitating the metastasis of breast cancer cells to the lungs, but very little is known about the role of fibroblasts during the complex process of metastases formation.

“In a normal situation, fibroblasts play a central role in healing wounds and injury to the lungs, but recent studies revealed that cancer is successful in recruiting them and causing them to produce a supportive environment for it,” explained Erez. “Within the framework of the present study, we performed sequencing of all the genes that are expressed (transcriptome sequencing) in fibroblasts taken from the lungs of mice in a model of breast cancer metastasis.”

The researchers compared the sequencing results sampled from healthy lungs, from lungs with micro-metastases (very small metastases which cannot be identified using existing clinical tools) and from lungs with large metastases in a state of advanced disease. According to the changes identified from stage to stage, the researchers succeeded, for the first time, in characterizing the process occurring in the micro-environment of the metastases, already in the early stages of preparation of the area for its reception. 

In addition, they specifically identified the proteins that initiate the “rewiring” processes in fibroblasts and discovered that one of the central proteins in the process is MYC, which is known as a central driver in accelerating the division of cancerous cells. The TAU study revealed that MYC also plays an important role in the changes occurring in fibroblasts towards reception of the metastases. 

“In our study, we have succeeded in characterizing processes which occur in lung tissue in preparation for the reception of breast cancer metastases,” she concluded. “We believe that in the future, our findings can aid in the identification of the metastatic process even before the disseminated cancer cells thrive and colonize the metastatic organ, with the purpose of providing prophylactic treatment. Such treatment, that will prevent the development of metastases, may save the lives of millions of people, worldwide.”