The Dianas Terapéuticas group is composed of two clinical professionals, both adjuncts of the Medical Oncology Service, a predoctoral student, a postdoctoral researcher, and a laboratory technician, in addition to the IP, which has a Miguel Servet II contract. The group has focused its work on the study of new molecular markers that could be used in clinical practice to improve prognosis and identify possible resistance to oncological treatments in colon and lung cancer.

Regarding colon cancer, the group began a line of research focused on the possible usefulness of type 2 cannabinoid receptor (CB2) expression as a possible prognostic marker in colon cancer and its possible use as a therapeutic target. Activation of this receptor was postulated, according to data published by other authors, as a good therapeutic strategy, since it induced cell cycle arrest and apoptosis. This was achieved in "in vitro" assays using high concentrations of agonists; however, our results in this regard are contradictory, as set out below. Firstly, we observed that this receptor was expressed in 28.6% of the patients analysed (175), and was a poor prognostic factor associated with lymph node involvement and significantly shorter survival, especially in patients with stage III tumours. We have verified, using cell models and a murine model, that its activation with high doses of agonists had antitumour effects; however, its activation with lower doses, more similar to endogenous conditions, had pro-tumour effects such as: increased proliferative rate, increased migratory activity, activation of the PI3K/AKT pathway, increased p-GSK3β levels, destabilisation of adherens junctions, delocalisation of β-catenin and increased SNAIL levels. In addition, in the patient series there was a direct correlation between CB2 expression and SNAIL levels. In parallel, we observed an increase in the migratory capacity of fibroblasts in the presence of conditioned media where epithelial cells overexpressing SNAIL had previously been expanded. This effect was also observed when epithelial cells were treated with CB2 agonists. We subsequently found that the cytokine MCP-1/CCL2, whose expression and release increases with CB2 activation or increased SNAIL, was responsible, at least in part, for the fibroblast-recruiting capacity towards the tumour environment. In addition, MCP1 is able to activate these same fibroblasts, as they increase α-SMA expression. In parallel with the increase in α-SMA, there is an increase in TWIST levels in fibroblasts and clear nuclear internalisation of this protein, a process involved in fibroblast activation. In human tumour samples we have observed a direct correlation between MCP-1 expression levels and SNAIL and α-SMA. This suggests that SNAIL overexpression in colon tumours induces MCP-1 overexpression, which acts as a fibroblast recruiting and activating agent. We have found that while CB2 is expressed in the tumour epithelial cell, TWIST is only expressed in tumour-associated fibroblasts, with a direct correlation between the expression of both proteins in our tumour series. Overall, this suggests that CB2 activation under pathophysiological conditions induces increased expression or stabilisation of SNAIL, which favours the release of MCP-1, which in turn contributes to fibroblast recruitment and activation.

In the case of lung cancer, we generated three lines resistant to cisplatin, two of which overexpress TWIST, a protein related in other studies to resistance to cisplatin. "De novo" exposure to cisplatin induces significant increases in the expression of TWIST, being more pronounced in the resistant lines than in the parental ones. In parallel to this process, a nuclear relocation of the protein is observed. With immunohistochemical markers of TWIST in human samples, we have detected cases where TWIST is expressed in an inconsistent manner in tumor epithelial cells. Thus, moderate labeling is observed in cells with a rounded phenotype, and a markedly more intense labeling in cells of the same tumor with a more fusiform phenotype. The cases that present this phenotype correspond to patients with significantly shorter progressions-free survival.
A line of research has been started focused on the role of energy metabolism in lung cancer, both in disease prognosis and in modifying treatment response and the search for new therapeutic targets. Within this line, we have recently published on the relevance of the PGC-1alpha gene and the different metabolic types in the prognosis of NSCLC patients. This work also identifies possible treatments targeting these metabolites.
These studies were carried out thanks to participation in the following projects: PI10/00879 Papel de mediadores de citoquinas reguladas por SNAIL en la activación y reclutamiento de fibroblastos en tumores. Relevancia en la evolución de enfermos con cáncer de colon, ISCIII. PIE 14/0064 Personalized Medicine in Oncology: researching a model capable of improving and predicting the result treatment based in molecular machanisms, tumor biology, images, IT and murine model. RD12/0036/0041. Red Temática de Investigación Cooperativa en Cáncer. Instituto de Salud Carlos III. 2013-2016. SS2010/BMD-2344. Transcriptoma, proteoma e interactoma en tejido epitelial y estromal del colon humano y sus alteraciones patológicas Colomics2-CM; Colomics2-CM. 2012-2015. H2020-727658. Integration and analysis of heterogeneous big data for precision medicine and suggested treatments for different type of patients. European Commission.