Researchers find recruitment mechanism for cancer-associated fibroblasts in the most common lung cancer

A team of experts led by Jordi Alcaraz, professor at the UB and associated researcher at IBEC, found a mechanism of recruitment for tumour-associated cells (cancer-associated fibroblasts or CAFs) which are essential to lung adenocarcinoma, the most frequent type of cancer. This finding is very relevant since the cancer-associated cells contribute to all the phases of tumour development, including metastasis. 

The study, published in the British Journal of Cancer, reveals there is a type of inhibitor drug which could be useful against the migratory advantage of these cancer-associated cells, so they could prevent their recruitment and therefore, their contribution to the tumour development. 

The study reveals how lung adenocarcinoma recruits cancer-associated cells and this process can favour cancer cells dissemination.

“The importance of these findings lies in the fact that lung adenocarcinoma represents 40% of the cases of lung cancer and it produces an early metastasis, which directly affects the patients’ chances of survival”

says lecturer Jordi Alcaraz, coordinator of the study and member of the Faculty of Medicine and Health Sciences of the UB and associated resercher at the Institute of Bioengineering of Catalonia (IBEC).

Now, the five-year survival rate for lung cancer that has not spread to other organs is over 60%. However, when it spreads to other parts of the body, these chances are reduced to below 10%. 

How does SMAD3 protein affect the tumour process? 

The expert Jordi Alcaraz, (UB-IBEC) found in previous studies that the SMAD3 protein is selectively overactivated in patients with adenocarcinoma. Now, the new study, conducted together with the University of Zaragoza, analyses the effects of the SMAD3 protein in the cancer-associated cell recruitment, and it analyses its impact in the tumour dissemination and metastasis generation. 

The team led by Professor José Manuel García Aznar, from the UZ University Research Institute on Engineering in Aragón (I3A), in which the researchers Yago Juste Lanas and Carlos Borau take part, applied an innovative technology based on microfluidic devices with 3D collagen extracellular matrices to study the cancer-cell protrusions and cell migration in environments that simulate different stages of tumour development. 

Cancer-associated cells showed a migratory advantage —faster and more directional movement— in an environment typical of the early stages of cancer. Also, the researchers saw in these cancer-associated cells, a lower proliferative capacity, which involved the SMAD3 promigratory effect as an essential factor for the recruitment and accumulation of CAFs in adenocarcinoma. As these cancer-associated cells contribute to all the phases of tumour development —including the dissemination—, this finding could be decisive for understanding the early dissemination of adenocarcinoma to other organs. Also, this migratory advantage was removed by the inhibitor Trametinib —already approved to be used in other types of tumours, which encourages its therapeutical use in lung adenocarcinoma. 

According to the expert Yago Juste Lanas, member of the UZ M2BE group and first author of the study, the researchers “found that the adenocarcinoma tumour-associated cells have a high migratory capacity. This enables their recruitment to the tumour more easily, and it could favour an early metastasis formation, a process observed in patients but for which the causes 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 tumour, researchers have stated that adenocarcinoma-associated cells can establish closer interactions with tumour cells due to the reduction of the migratory capacity seen in this study. “We continue to work to understand whether lung adenocarcinoma-associated cells can also promote the spread of these tumours by other mechanisms, with the ultimate aim of curbing their metastasis”. 

A multidisciplinary collaborative research 

The participation of doctors, biotechnologists, physicists and engineers has been decisive for this multidisciplinary collaborative research to succeed. In particular, the Hospital Clínic de Barcelona provided the patients’ biopsies, which were used by the UB teams to obtain the cancer-associated cells and to study molecular alterations such as the SMAD3 case. Also, the UZ teams studied the movement of this cell type in physiopathological environments similar to those found in early and late stages of the tumour development. 

Other experts signing the study are Carlos Borau (UZ); Natalia Díaz-Valdivia and Alejandro Llorente (UB-IBEC); Rafael Ikemori, Alejandro Bernardo and Marselina Arshakyan (UB), Josep Ramírez (Hospital Clínic de Barcelona); José Carlos Ruffinelli and Ernest Nadal (ECO-IDIBELL) and Noemí Reguart (Hospital Clínic-IDIBAPS). 

Reference article: 

Juste-Lanas, Y., Díaz-Valdivia, N., Llorente, A., Ikemori R., Bernardo, A., Arshakyan, Borau, C., Ramírez, J., Ruffinelli, J.C., Nadal, E., Reguart, N., García-Aznar, J.M. & Alcaraz, J. 3D collagen migration patterns reveal a SMAD3-dependent and TGF-β1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma. British Journal of Cancer (2022). DOI: 10.1038/s41416-022-02093-x