A mechanism for recruiting helper cells (called CAFs or cancer-associated fibroblasts) has been discovered, which are essential for lung adenocarcinoma, the most common type of cancer. This finding is highly relevant, since helper cells contribute to all phases of tumor development, including metastasis.
The discovery was made by a team of experts from the University of Barcelona (UB), the Hospital Clínic de Barcelona and the University of Zaragoza, in Spain.
The study carried out by these scientists also reveals that there is a type of inhibitor drug that could be useful against the migratory capacity of these helper cells, thus preventing their recruitment and, therefore, their subsequent contribution to tumor development.
“The importance of these two findings lies in the fact that lung adenocarcinoma represents 40% of lung cancer cases and produces very early metastasis, a fact that directly affects the chances of survival of patients”, details the Professor Jordi Alcaraz, coordinator of the work and member of the Faculty of Medicine and Health Sciences of the UB and the Institute of Bioengineering of Catalonia (IBEC). Currently, the five-year survival probability for lung cancer that has not spread to other organs is greater than 60%. Now, when it has reached other parts of the body, the chances are reduced to less than 10%.
Alcaraz discovered in previous studies that the SMAD3 protein is selectively overactivated in patients with adenocarcinoma. Now, the new study examines the effects of the SMAD3 protein on the recruitment of helper cells, and analyzes its impact on tumor spread and metastasis generation.
To achieve this, the group led by Professor José Manuel García Aznar, from the University Institute for Engineering Research in Aragón (I3A) of the University of Zaragoza, in which the researchers Yago Juste Lanas and Carlos Borau participate, applied an innovative technology based on microfluidics with collagen extracellular matrices in 3D, in order to study attendant cell protrusions and cell migration in environments that simulate different stages of tumor development.
From left to right, researchers Carlos Borau Zamora, Yago Juste Lanas (center) and José Manuel García Aznar, from the University of Zaragoza. (Photo: University of Zaragoza. CC BY)
The assisting cells showed a migratory advantage —faster and more directional movement, with more elongated shapes— in an environment typical of the initial stages of the tumor. Likewise, a lower proliferative capacity was observed in these helper cells, a fact that implied the promigratory effect of SMAD3 as an essential factor for the recruitment and accumulation of CAF helper cells in adenocarcinomas. Since these helper cells contribute to all phases of tumor development—including spread—this finding could be critical to better understand the early spread of adenocarcinoma to other organs. In addition, this migratory advantage was eliminated by the inhibitor drug Trametinib, already approved for use in other types of tumors, a fact that encourages the therapeutic use of this type of drug in lung adenocarcinoma.
“We have discovered that the helper cells of adenocarcinoma tumors have a high migratory capacity”, sums up Yago Juste Lanas, a member of the M2BE group at the University of Zaragoza and co-author of the new study. “This allows them to be more easily recruited to the tumor, and could favor the early formation of metastases, a process that is observed in patients, but the causes of which are still unknown. In addition, inhibitors such as trametinib, according to our results, could be effective against recruitment.”
In environments close to a more developed tumor, it has been found that the helper cells of adenocarcinomas can establish closer interactions with the tumor cells due to the reduction in the migratory capacity observed in this study. “We are continuing to work to understand if the helper cells of lung adenocarcinoma can also favor the spread of these tumors by other mechanisms, with the ultimate goal of being able to stop their metastasis.”
Multidisciplinary collaborative research
For the success of the research, a multidisciplinary collaborative project, the participation of experts from many different fields, including doctors, biotechnologists, physicists and engineers, has been decisive. Specifically, the Hospital Clínic de Barcelona provided the biopsies of the patients, which were used by the UB teams to obtain assisting cells and to be able to study their molecular alterations, as in the case of SMAD3. On the other hand, the teams from the University of Zaragoza have studied the movement of this type of cell in pathophysiological environments similar to those found in the initial or late stages of tumor development.
Also signing the work are Natalia Diaz-Valdivia and Alejandro Llorente (UB-IBEC); Rafael Ikemori, Alexander Bernard and Marcelina Arshakyan (UB), Josep Ramirez (Barcelona Clinical Hospital); Jose Carlos Ruffinelli and Ernest Nadal (ECO-IDIBELL) and Naomi Reguart (Clinical Hospital-IDIBAPS).
The study is titled “3D collagen migration patterns reveal a SMAD3-dependent and TGF-β1-independent mechanism of recruitment for tumor-associated fibroblasts in lung adenocarcinoma”. And it has been published in the academic journal British Journal of Cancer. (Source: UB)
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