Periodic Reporting for period 4 - CancerADAPT (Targeting the adaptive capacity of prostate cancer through the manipulation of transcriptional and metabolic traits)
Período documentado: 2024-05-01 hasta 2025-10-31
CancerADAPT was conceived to spearhead the identification of prostate cancer vulnerabilities through the integration of clinical studies, experimental modeling and computational biology. The proposal has contributed to the identification of mechanisms by which cancer cells adapt to hostile environments existing in our body. The common theme of the projects develop in the context of this proposal is adaptation. The adaptive properties of a tumor pertain the molecular alterations that support the acquisition of new features by cancer cells, which contribute to disease manifestation, progression, dissemination or treatment response. CancerADAPT undertakes this ambitious goal through the implementation of computational approaches to maximize the exploitation of data from curated prostate cancer clinical datasets and high-throughput molecular studies in experimental cancer models. Bioinformatics integration provides us with the opportunity to increasing the granularity of our analyses, and to build hypotheses that can be validated and mechanistically deconstructed using in vitro and in vivo systems. The ultimate goals of CancerADAPT are i) to increase our fundamental understanding of the molecular bottlenecks of prostate tumors to gain aggressive features, and ii) exploit the information about the adaptive processes that are critical for aggressive prostate tumors in order to devise therapeutic strategies that improve patient management. We believe that only the fundamental understanding of the biological processes underlying cancer biology can lead to the identification of innovative combinatorial therapies.
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.
- 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.
Our research has unraveled potential processes that underlie the adaptation of prostate cancer cells to hostile environments during the process of disease progression.
We enumerate some of the findings that have pushed the field of cancer metabolism forward beyond the state of the art, and future lines that are being developed as a consequence of CancerADAPT:
• We have identified a series of molecular effectors that promote or suppress prostate cancer progression
• We have unveiled a metabolic crosstalk between tumor and stromal cells that support the cancer cell adaptation and the acquisition of aggressive features.
• We have generated novel mouse models of metastatic prostate cancer that recapitulate unique features of the most aggressive variant of this disease.
• We are continuing to study the contribution of systemic metabolic alterations to the adaptation to androgen deprivation in prostate cancer as a critical step behind castration resistant prostate cancer.
• We have defined a new mechanism through which polyamines regulate protein function and epigenetic regulation.
• We have found molecular alterations in the perivascular cells that are associated to vessel changes and alterations in vascular homeostasis and tumor cell intravasation.
• We have studied the role of androgens in remodeling prostate cancer cell metabolism.
We enumerate some of the findings that have pushed the field of cancer metabolism forward beyond the state of the art, and future lines that are being developed as a consequence of CancerADAPT:
• We have identified a series of molecular effectors that promote or suppress prostate cancer progression
• We have unveiled a metabolic crosstalk between tumor and stromal cells that support the cancer cell adaptation and the acquisition of aggressive features.
• We have generated novel mouse models of metastatic prostate cancer that recapitulate unique features of the most aggressive variant of this disease.
• We are continuing to study the contribution of systemic metabolic alterations to the adaptation to androgen deprivation in prostate cancer as a critical step behind castration resistant prostate cancer.
• We have defined a new mechanism through which polyamines regulate protein function and epigenetic regulation.
• We have found molecular alterations in the perivascular cells that are associated to vessel changes and alterations in vascular homeostasis and tumor cell intravasation.
• We have studied the role of androgens in remodeling prostate cancer cell metabolism.