The work performed under the umbrella of this funding scheme has enabled us to identify molecular processes that support the acquisition of aggressive features in tumors. Importantly, these molecular alterations pertain both to the tumor cells and to the non-cancerous cells in the stroma. We enumerate the strategies that we have followed to build an innovative research strategy during the execution of our proposal.
- We have gathered, integrated and generated molecular datasets of prostate cancer patient cohorts to identify potential mediators of prostate cancer progression. We have exploited this rich clinical resource using advanced computational strategies in order to identify molecular events that are consistently altered in recurrent of metastatic disease. Tumor and stromal candidates emanating from this strategy have been validated and molecularly analyzed, which has led to various international peer-reviewed publications, and to dissemination in scientific and lay public activities.
- Identifying effectors of androgen signaling and adaptation to androgen deprivation. Prostate cancer patients are frequently treated with androgen-deprivation therapies once they fail to respond to first line treatments. However, resistance often emerges, leading to castration-resistant prostate cancer. We have studied metabolic perturbations that are regulated by androgens to shed light on the mechanism that might lead to resistance to androgen deprivation therapies. Conversely, work performed during CancerADAPT has unraveled a contribution of systemic metabolic alterations in the acquisition of resistance to androgen deprivation therapy. Some of these studies have been published in international journals and presented in conferences, and received recognitions in the form of best poster communication.
- Unraveling the mechanism of action of key metabolic drivers of prostate cancer progression. We have identified, characterized and modelled metabolic perturbations in prostate cancer to address their role in the pathogenesis and progression of the disease. This strategy has allowed us to ascertain the tumor suppressive role of LKB1 in metastatic prostate cancer, the role of fibroblastic aspartoacylase in the remodeling of the prostate tumor stroma or the contribution of PGC1A to prostate cancer suppression. In addition to the advance in knowledge generated by these projects, they have also led to the generation of model system that replicate better specific aspects of prostate cancer. For example, a mouse model of prostate cancer resulting from loss of PTEN and LKB1 has allowed us to generate a prostate cancer model of metastatic hormone naïve prostate cancer, an infrequent type of prostate cancer (10% of incidence) that accounts for up to 50% of prostate-cancer-related mortality. These studies led to various international peer-reviewed publications, to dissemination in scientific and lay public activities, and to the establishment of collaboration with pharmaceutical companies.
- Identification of adaptive epigenetic processes that are activated upon metabolic deregulation. The connection between metabolic processes and epigenetic regulation is a highly active field of research. CancerADAPt has inspired the search for novel effectors of a metabolic pathway that is relevant for prostate cancer oncogenicity, namely polyamine biosynthesis. We have discovered that this family of metabolites recognize specific protein motifs and regulate the access of kinases to phosphorylates this region. We have termed this process “metabolic shielding”. The relevance of this finding is supported by its recent acceptance for publication in Nature, and has generated new research lines that are being pursued in the lab.
