Adverse events in CA-3 vs vehicle treated mice

Inhibition of α2 reduces invasiveness of PNE and PAC cells

Divergence of the proteomes of ECMs obtained from TRAMP and WT prostates

Polarized light analysis of ECM linearization in human prostate cancer specimen

Differentially expressed matrisome genes discriminate human NEPC and CRPC-Adeno

Gene signatures used for transcriptomic analysis

Upregulation of integrin α2 is characteristic of PNE and not PAC cells

PNE cells translocate YAP into the nucleus when cocultured with PAC cells

Abstract The emergence of the neuroendocrine phenotype in castration-resistant prostate cancer (CRPC) is associated with poor patient prognosis. Castration-induced death of fully differentiated, androgen-sensitive prostate cancer cells might foster interactions among rare androgen-independent, poorly differentiated cancer cells and the extracellular matrix (ECM) that promotes the development of neuroendocrine prostate cancer (NEPC). In this study, we investigated physical and molecular interactions between poorly differentiated prostate cancer cells with exocrine (PAC) or neuroendocrine features (PNE), which recapitulated preexisting human CRPC-like cells, and decellularized prostate ECM. Without androgens, PAC cells and prostate cancer–derived ECM promoted in vitro invasiveness of PNE cells by inducing integrin α2 upregulation and YAP activation, indicating a cell-to-cell and cell-to-matrix contact-driven process. Inhibition of RANK/RANKL and NF-κB prevented integrin α2 upregulation in PNE cells, and integrin α2β1 and YAP inhibition also reduced PNE invasiveness. Microenvironment-conditioned PNE cells showed YAP-dependent metastatic behavior in vivo, and YAP inhibition suppressed the development of NEPC and metastasis in castration-naïve mice and of neuroendocrine CRPC in transgenic mice with prostate cancer. Importantly, YAP inhibitors also restrained the growth of human CRPC organoids. These findings unveil mechanisms of NEPC development and implicate the integrin α2–YAP axis as a therapeutic target in patients with prostate cancer receiving androgen deprivation therapy. Significance: Targeting signaling pathways activated by interactions between poorly differentiated neuroendocrine and exocrine prostate cancer cells and the surrounding ECM suppresses NEPC development and metastasis.

Signature of pre-existing CRPC-like cells segregates NEPC from adenocarcinoma in mice and humans

Efficacy of CA-3 treatment in mouse models of PC

CA-3 inhibits NEPC and not WT organoids

α2 upregulation requires cell-to-cell contact and NF-kB signaling

CRPC (AR-high) and luminal (PSA-low) co-express YAP1 and NE markers

Identified proteins in the mouse ECM

Obesity is associated with a decrease in chemosensory perception acuity and increased disease risk, pointing to the need for feasible interventions that affect smell, taste, and cardiometabolic markers. Here, subjects with overweight/obesity are treated with six monthly cycles of a fasting-mimicking diet (FMD) lasting 5 days followed by a normal diet for the rest of the month to determine their effects on chemosensory function and cardiometabolic risk factors. Both arms of the 102 randomized cross-over trial participants indicate FMD-dependent improvements in a wide range of taste and smell chemosensory functions. The portion of hyposmic subjects is reduced from 38.1% at baseline to 6.4% at the end of 6 FMD cycles. FMD cycles also reduce cardiometabolic and inflammatory markers and drug use in diabetic patients. This trial provides evidence for the effect of periodic FMD cycles in improving chemosensory function while reducing cardiometabolic risk factors without requiring long-term lifestyle changes. The trial is registered at ClinicalTrials.gov (NCT04529161).

WB analyses of EBI3 protein expression and ELISA assay (THP-1 cells were uses as positive control) to detect EBI3 in wild type PIN-SC supernatant.

Differences in gustatory sensitivity, nutritional habits, circulating levels of modulators, anthropometric measures, and metabolic assays may be involved in overweight (OW) development. The present study aimed at evaluating the differences in these aspects between 39 OW (19 female; mean age = 53.51 ± 11.17), 18 stage I (11 female; mean age = 54.3 ± 13.1 years), and 20 II (10 female; mean age = 54.5 ± 11.9) obesity participants when compared with 60 lean subjects (LS; 29 female; mean age = 54.04 ± 10.27). Participants were evaluated based on taste function scores, nutritional habits, levels of modulators (leptin, insulin, ghrelin, and glucose), and bioelectrical impedance analysis measurements. Significant reductions in total and subtests taste scores were found between LS and stage I and II obesity participants. Significant reductions in total and all subtests taste scores were found between OW and stage II obesity participants. Together with the progressive increase in plasmatic leptin levels, insulin, and serum glucose, decrease in plasmatic ghrelin levels, and changes in anthropometric measures and nutritional habits along with body mass index, these data for the first time demonstrated that taste sensitivity, biochemical regulators, and food habits play a parallel, concurring role along the stages evolving to obesity.

Supplementary Figures S1-S6. Representative dot plots of in vitro inhibition of T cell activation by TPIN-SCs (S1); Non-irradiated TPIN-SCs arrest in vitro T cell activation (S2); TPIN-SCs inhibit restimulation of antigen-experienced T cells but do not affect fully activated T cells (S3); TPIN-SC-conditioned T cells are hyporesponsive (S4); Silencing of TNC modulates the inhibitory activity of TPIN-SCs (S5); CSCs migration is mediated by the CXCR4/CXCL12 axis (S6).

Immunohistochemical analyses of Sca-1 expression in subcutaneously developed EV-IL-30PIN-SC and IL-30PIN-SC tumors compared with EV-IL-30PIN-SC and IL-30PIN-SC orthotopic tumors.*p<0.05 by Student's t test compared with EV-IL-30PIN-SC Sc. **p<0.05 by Student's t test compared with IL-30PIN-SC Sc. and EV-IL-30PIN-SC Ortho.