Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 Inhibitors.
Matthew J MosqueraSungwoong KimRohan BarejaZhou FangShuangyi CaiHeng PanMuhammad AsadMaria Laura MartinMichael SigourosFlorencia M RowdoSarah AckermannJared CapuanoJacob BernheimCynthia CheungAshley DoaneNicholas BradyRicha SinghDavid S RickmanVarun PrabhuJoshua E AllenLoredana PucaAhmet F CoskunMark A RubinHimisha BeltranJuan Miguel MosqueraOlivier ElementoAnkur SinghPublished in: Advanced materials (Deerfield Beach, Fla.) (2021)
Following treatment with androgen receptor (AR) pathway inhibitors, ≈20% of prostate cancer patients progress by shedding their AR-dependence. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). No targeted therapies are available for CRPC-NEPCs, and there are minimal organoid models to discover new therapeutic targets against these aggressive tumors. Here, using a combination of patient tumor proteomics, RNA sequencing, spatial-omics, and a synthetic hydrogel-based organoid, putative extracellular matrix (ECM) cues that regulate the phenotypic, transcriptomic, and epigenetic underpinnings of CRPC-NEPCs are defined. Short-term culture in tumor-expressed ECM differentially regulated DNA methylation and mobilized genes in CRPC-NEPCs. The ECM type distinctly regulates the response to small-molecule inhibitors of epigenetic targets and Dopamine Receptor D2 (DRD2), the latter being an understudied target in neuroendocrine tumors. In vivo patient-derived xenograft in immunocompromised mice showed strong anti-tumor response when treated with a DRD2 inhibitor. Finally, we demonstrate that therapeutic response in CRPC-NEPCs under drug-resistant ECM conditions can be overcome by first cellular reprogramming with epigenetic inhibitors, followed by DRD2 treatment. The synthetic organoids suggest the regulatory role of ECM in therapeutic response to targeted therapies in CRPC-NEPCs and enable the discovery of therapies to overcome resistance.
Keyphrases
- extracellular matrix
- dna methylation
- prostate cancer
- drug resistant
- small molecule
- gene expression
- genome wide
- radical prostatectomy
- single cell
- multidrug resistant
- neuroendocrine tumors
- drug delivery
- squamous cell carcinoma
- transcription factor
- acinetobacter baumannii
- mass spectrometry
- combination therapy
- long non coding rna
- radiation therapy
- case report
- metabolic syndrome
- rna seq
- peripheral blood
- hyaluronic acid
- high throughput
- wound healing
- newly diagnosed
- insulin resistance
- cystic fibrosis
- replacement therapy
- rectal cancer
- respiratory failure