Timing of treatment shapes the path to androgen receptor signaling inhibitor resistance in prostate cancer.

There is optimism that cancer drug resistance can be addressed through appropriate combination therapy, but success requires understanding the growing complexity of resistance mechanisms, including the evolution and population dynamics of drug-sensitive and drug-resistant clones over time. Using DNA barcoding to trace individual prostate tumor cells in vivo , we find that the evolutionary path to acquired resistance to androgen receptor signaling inhibition (ARSI) is dependent on the timing of treatment. In established tumors, resistance occurs through polyclonal adaptation of drug-sensitive clones, despite the presence of rare subclones with known, pre-existing ARSI resistance. Conversely, in an experimental setting designed to mimic minimal residual disease, resistance occurs through outgrowth of pre-existing resistant clones and not by adaptation. Despite these different evolutionary paths, the underlying mechanisms responsible for resistance are shared across the two evolutionary paths. Furthermore, mixing experiments reveal that the evolutionary path to adaptive resistance requires cooperativity between subclones. Thus, despite the presence of pre-existing ARSI-resistant subclones, acquired resistance in established tumors occurs primarily through cooperative, polyclonal adaptation of drug-sensitive cells. This tumor ecosystem model of resistance has new implications for developing effective combination therapy.

Next-Generation Modeling of Cancer Using Organoids.

In the last decade, organoid technology has become a cornerstone in cancer research. Organoids are long-term primary cell cultures, usually of epithelial origin, grown in a three-dimensional (3D) protein matrix and a fully defined medium. Organoids can be derived from many organs and cancer types and sites, encompassing both murine and human tissues. Importantly, they can be established from various stages during tumor evolution and recapitulate with high accuracy patient genomics and phenotypes in vitro, offering a platform for personalized medicine. Additionally, organoids are remarkably amendable for experimental manipulation. Taken together, these features make organoids a powerful tool with applications in basic cancer research and personalized medicine. Here, we will discuss the origins of organoid culture, applications in cancer research, and how cancer organoids can synergize with other models of cancer to drive basic discoveries as well as to translate these toward clinical solutions.

Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling.

Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.