Abstract C056: Characterization of prostate cancer secretomes for therapeutic intervention

Abstract

Abstract Introduction: Prostate cancer (PC) is a common malignancy among men, often driven by dysregulated androgen receptor (AR) signaling. Earlier stages of PC can be favorably treated with androgen deprivation therapies or AR signaling inhibitors. Unfortunately, metastatic PC (mPC) is currently incurable. Neuroendocrine prostate cancer (NEPC) is a subgroup of mPC that may be derived as result of transdifferentiation of adenocarcinomas, after AR-directed treatment. Previous studies using preclinical models have suggested a potentially beneficial relationship between NEPC and AR-active prostate cancer (ARPC) cells. We hypothesize that secreted factors derived from NEPC cells influence local, and distant ARPC cell types to promote treatment resistance. Methods: Five NEPC in vitro cell models: NCI-H660, MSKCC-EF1, LTL331R, LuCaP-49 and LuCaP-173.1 were maintained in serum free media for 24 hours. The conditioned media (CM) was then collected and admixed with growth medium for ARPC cells. The ARPC growth medium was either supplemented with Fetal Bovine Serum (FBS) or Charcoal Stripped fetal bovine Serum (CSS). GFP-labelled ARPC cells: LnCaP and C42B were seeded in the respective media admixed with the CM. The viability of cells was measured using a Cytation5 microplate reader. We implemented a transcriptomic (RNAseq) and mass-spectrometry based proteomic analysis to identify differentially expressing secretory proteins that could have an impact on the treatment resistance of ARPC cell types. Results: All 5 NEPC-CM showed qualitative growth promoting effects towards ARPC C42B cells grown in CSS supplemented media. Only CM from EF1 and H660 promoted the growth of ARPC C42B in FBS supplemented media. NEPC-CM did not affect growth of LnCaP ARPC cells. Mass-spectrometry for secreted proteins was performed on 3 NEPC cell models. Analysis of the proteins against the PANTHER gene ontology database shows: (i) cell communication, and (ii) cellular response to stimulus,  as two important biological processes active in NEPC. Genes involved in the two pathways were further compared against a comprehensive transcriptomic dataset spanning distinct mPC phenotypes and genotypes. Neurotrophic growth factors: Brain-derived growth factor (BDNF), Nerve-growth factor (NGF), VGF and neurotrophin-3 (NT-3) emerged as important targets that were differentially expressed in NEPC versus ARPC cells. Conclusions: NEPC cells have the potential to influence ARPC phenotypes that include enhanced proliferation, AR targeting, and potentially other drug resistance programs. As mPC exhibits substantial intra-individual and intra-tumor heterogeneity, understanding a targeting heterotypic cell interactions could lead to new druggable targets and address treatment resistance resulting from complex inter-cellular interactions. (Funding: PC220408) Citation Format: Tarana Arman, Lisa A. Jones, Ilsa M. Coleman, Philip R. Gafken, Peter S. Nelson. Characterization of prostate cancer secretomes for therapeutic intervention [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C056.