1) Identification of key molecular alterations and characterization of intratumor heterogeneity (ITH) and tumor evolution in large series of cancer samples using state-of the-art high throughput genomic analysis technologies.
2) Discovery and validation of prognostic and predictive markers using molecular pathology techniques (e.g. immunohistochemistry, mutation analysis) in cancer cohorts (cancer biopsies, patient-derived-xenografts) with clinical information.
3) Definition of the precise biological and biochemical mechanisms of key molecular alterations and their impact in the clinical behavior of cancers with the aim of subsequently developing novel targeted treatments using innovative methods (including nanotechnology).
Covering all these three purposes, in the last 10 years our group has pioneered the identification of Gasdermin-B (GSDMB) over-expression as key mediator of tumor aggressiveness, metastasis, poor prognosis and unfavorable clinical response to treatment in HER2-positive breast cancers.
GSDMB, like other Gasdermin family proteins, can mediate either pro-tumor (invasion, metastasis, resistance to therapy) or anti-tumor (including the lytic and inflammatory cell death mechanisms termed pyroptosis) functions depending on the biological context. In this sense, as continuation of this line of research we have generated multiple in vitro and in vivo pre-clinical models that will be used to investigate the following key aspects:
- Detailed functional characterization of the molecular and cellular mechanisms regulating the diverse GSDMB (pro-tumor and antitumor) activities on healthy and cancer cells.
- Application of GSDMB over-expression as an innovative therapeutic target in HER2 positive tumors. Further development of improved anti-GSDMB nanotherapies.
- Validation of the GSDMB biological effects (such as response to treatment) observed in vitro and in vivo in diverse cohorts of human tumors (including PDX).
Furthermore, Dr. G Dominguez leads a project focussed on the involvement of DNp73, a member of the p53 family, in the different stages of the progression of colorectal cancer and in the response to treatments and the identification of its effector targets. In addition, she is also involved in the characterization of the molecular and cellular mechanisms of the peritoneal metastasis of colorectal cancer. This will help us identify possible therapeutic targets that can be transferred to the clinical practice.