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An Integrated Proteomic Portrait of Prostate Cancer Progression

ABSTRACT: Cancer forms a local tumor that subsequently metastasizes to distant organs. In prostate cancer, the latter part of the trajectory is influenced by the inhibition of the androgen receptor (AR). The study of proteomic changes along disease progression may reveal insights into how prostate cancer evolves and open new therapeutic avenues. Here, we profile changes in protein abundance and post-translational modifications (PTMs) along the disease trajectory in patient-derived xenograft models. Our results suggest a key involvement of the RTK-RAS-MAPK pathway during disease progression. We highlight multiple alterations within this pathway including the tumor suppressors NF1 and ERF. Enhanced activity of cyclin-dependent kinases results in the engagement of various DNA repair pathways. Specific PTMs suggest changes in mitochondrial ATP synthesis, proteasomal activity, gene splicing, and TGF beta signaling. Finally, we show how different transcription factors engage with disease progression. A web resource is provided enabling the investigation of dynamic proteomic perturbations.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jean-Philippe Theurillat

PROVIDER: MSV000096252 | MassIVE | Wed Oct 30 13:51:00 GMT 2024

REPOSITORIES: MassIVE

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Project description:Following androgen ablation therapy (AAT), the vast majority of prostate cancer patients develop treatment resistance with a median time of 18-24 months to disease progression. To identify molecular targets that aid in prostate cancer cell survival and contribute to the androgen independent phenotype, we evaluated changes in LNCaP cell gene expression during 12 months of androgen deprivation. At time points reflecting critical growth and phenotypic changes, we performed Affymetrix expression array analysis to examine the effects of androgen deprivation during the acute response, during the period of apparent quiescence, and during the emergence of highly proliferative, androgen-independent prostate cancer cells (LNCaP-AI). We discovered alterations in gene expression for a host of molecules associated with promoting prostate cancer cell growth and survival, regulating cell cycle progression, apoptosis and adrenal androgen metabolism, in addition to AR co-regulators and markers of neuroendocrine disease. These findings illustrate the complexity and unpredictable nature of cancer cell biology and contribute greatly to our understanding of how prostate cancer cells likely survive AAT. The value of this longitudinal approach lies in the ability to examine gene expression changes throughout the cellular response to androgen deprivation; it provides a more dynamic illustration of those genes which contribute to disease progression in addition to specific genes which constitute a malignant androgen-independent phenotype. In conclusion, it is of great importance that we employ new approaches, such as the one proposed here, to continue exploring the cellular mechanisms of therapy resistance and identify promising targets to improve cancer therapeutics. Experiment Overall Design: To identify molecular targets that aid in prostate cancer cell survival and contribute to the androgen independent phenotype, we evaluated changes in LNCaP cell gene expression during 12 months of androgen deprivation. At time points reflecting critical growth and phenotypic changes, we performed Affymetrix expression array analysis to examine the effects of androgen deprivation during the acute response, during the period of apparent quiescence, and during the emergence of highly proliferative, androgen-independent prostate cancer cells (LNCaP-AI).

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An Integrated Proteomic Portrait of Prostate Cancer Progression

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