Wnt signaling driven by genomic alterations in genes including APC and CTNNB, which encodes β-catenin, have been implicated in prostate cancer development and progression to metastatic castration-resistant prostate cancer (mCRPC). However, nongenomic drivers and downstream effectors of Wnt signaling in prostate cancer and the therapeutic potential of targeting this pathway in prostate cancer have not been fully established. Here we analyzed Wnt/β-catenin signaling in prostate cancer and identified effectors distinct from those found in other tissues, including aryl hydrocarbon receptor and RUNX1, which are linked to stem cell maintenance, and ROR1, a noncanonical Wnt5a coreceptor. Wnt/β-catenin signaling–mediated increases in ROR1 enhanced noncanonical responses to Wnt5a. Regarding upstream drivers, APC genomic loss, but not its epigenetic downregulation commonly observed in prostate cancer, was strongly associated with Wnt/β-catenin pathway activation in clinical samples. Tumor cell upregulation of the Wnt transporter Wntless (WLS) was strongly associated with Wnt/β-catenin pathway activity in primary prostate cancer but also associated with both canonical and noncanonical Wnt signaling in mCRPC. IHC confirmed tumor cell WLS expression in primary prostate cancer and mCRPC, and patient-derived prostate cancer xenografts expressing WLS were responsive to treatment with Wnt synthesis inhibitor ETC-1922159. These findings reveal that Wnt/β-catenin signaling in prostate cancer drives stem cell maintenance and invasion and primes for noncanonical Wnt signaling through ROR1. They further show that autocrine Wnt production is a nongenomic driver of canonical and noncanonical Wnt signaling in prostate cancer, which can be targeted with Wnt synthesis inhibitors to suppress tumor growth. Significance: This work provides fundamental insights into Wnt signaling and prostate cancer cell biology and indicates that a subset of prostate cancer driven by autocrine Wnt signaling is sensitive to Wnt synthesis inhibitors.

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Noncanonical Wnt signaling by WNT5a has oncogenic and tumor suppressive activities, but downstream pathways mediating these specific effects remain to be fully established. In a subset of prostate cancer organoid culture and xenograft models, inhibition of Wnt synthesis stimulated growth, while WNT5a or a WNT5a mimetic peptide (Foxy5) markedly suppressed tumor growth. WNT5a caused a ROR2-dependent decrease in YAP1 activity that was associated with increased phosphorylation of MST1/2, LATS1, MOB1, and YAP1, indicating Hippo pathway activation. Deletion of MST1/2 abrogated the WNT5a response. WNT5a similarly activated Hippo in ROR2-expressing melanoma cells, while WNT5a in ROR2-negative cells suppressed Hippo. This suppression was associated with increased inhibitory phosphorylation of NF2/Merlin that was not observed in ROR2-expressing cells. WNT5a also increased mRNA encoding Hippo pathway components including MST1 and MST2 and was positively correlated with these components in prostate cancer clinical datasets. Conversely, ROR2 and WNT5a expression were stimulated by YAP1, and correlated with increased YAP1 activity in clinical datasets, revealing a WNT5a/ROR2 negative feedback loop to modulate YAP1 activity. Together these findings identify Hippo pathway activation as a mechanism that mediates the tumor suppressive effects of WNT5a and indicate that expression of ROR2 may be a predictive biomarker for responsiveness to WNT5a-mimetic drugs.

Myeloproliferative neoplasms (MPNs) driver mutations are usually found in JAK2, MPL and CALR genes, however, 10–15% of cases are triple negative (TN). A previous study showed lower rate of JAK2 V617F in Primary Myelofibrosis (PMF) patients exposed to low doses of ionizing radiation (IR) from Chernobyl accident. To examine distinct driver mutations, we enrolled 281 Ukrainian IR-exposed and unexposed MPN patients. Genomic DNA was obtained from peripheral blood leukocytes. JAK2 V617F, MPL W515, type 1- and 2-like CALR mutations were identified by Sanger Sequencing and RT-PCR. Chromosomal alterations were assessed by oligo-SNP microarray platform. Additional genetic variants were identified by whole exome and targeted sequencing. Statistical significance was evaluated by Fisher’s exact test and Wilcoxon’s rank sum test (R, version 3.4.2). IR-exposed MPN patients exhibited a different genetic profile versus unexposed: lower rate of JAK2 V617F (58.4% vs 75.4%, P = 0.0077), higher rate of type 1-like CALR mutation (12.2% vs 3.1%, P = 0.0056), higher rate of TN cases (27.8% vs 16.2%, P = 0.0366), higher rate of potentially pathogenic sequence variants (mean numbers: 4.8 vs 3.1, P = 0.0242). Furthermore, we identified several potential drivers specific to IR-exposed TN MPN patients: ATM p.S1691R with copy-neutral loss of heterozygosity at 11q; EZH2 p.D659G at 7q and SUZ12 p.V71M at 17q with copy number loss. Thus, IR-exposed MPN patients represent a group with distinct genomic characteristics worthy of further study.

Summary. Aim: To examine frequencies and spectrum of genomic alterations in Ukrainian patients diagnosed with primary myelofibrosis (PMF). Materials and Methods: We enrolled 30 Ukrainian patients diagnosed with PMF who were previously tested for usual mutations in mye­loproliferative neoplasms driver genes (JAK2, MPL and CALR). Genomic DNA samples were obtained from peripheral blood leukocytes of these patients. Copy number alterations and copy-neutral loss of heterozygosity (cnLOH) were assessed using a high-density CytoScan HD microarray platform. Statistical significance was evaluated by the Fisher exact test. Results: We identified frequent genomic alterations, but no significant difference in the rates of copy-number loss, copy-number gain, cnLOH, or multiple genomic alterations were found in the groups of PMF patients that were positive for one of the usual mutations in driver genes or negative for such mutations (33.3% and 55.6%, p = 0.4181, 19.0% and 11.1%, p = 1.0000, 61.9% and 44.4%, p = 0.4434, 33.3% and 55.6%, p = 0.4181, respectively). The most frequent alterations were cnLOH at 1p36-1p22, 9p24.3-9p13.3 and 11q12.3-11q25; copy number loss at 7q21-7q36.3 and 13q12.3-13q14.3. Copy number alterations and cnLOH commonly affected the EZH2, LAMB4, CBL, CUX1, ATM, RB1 and TP53 genes, in addition to JAK2, MPL and CALR. Conclusion: We demonstrated the spectrum of genomic alterations in the groups of the Ukrainian PMF patients with or without the usual mutations in the specific driver genes. We identified several potential genes, which may be involved in the myeloproliferative neoplasms development and their phenotype modification (EZH2, LAMB4, CBL, CUX1, ATM, RB1 and TP53).

Objective. To investigate the intensity of burdensome symptoms using self assessment MPN SAF TSS in patients with radiation associated and spontaneous myeloproiliferative neoplasms (MPNs). Materials and methods. The study included 89 patients with radiation associated and spontaneous MPNs, the bur densome symptoms of MPN were determined using MPN SAF TSS. Results. The average score for complaints in patients with radiation associated MPNs was significantly higher than in patients with spontaneous MPNs -43.46 and 25.04 points, respectively (p = 0.003). MPN patients classified by subtypes also showed differences regarding intensity of burdensome MPN symptoms, demonstrating significantly higher average score of complaints among primary myelofibrosis patients (35.60), compared to polycythemia vera (29.60) and essential thrombocythemia (18.05) patients, (p = 0.005). Our study did not reveal any influence of the JAK2 V617F mutation on MPN burdensome symptoms intensity in MPN patients. Conclusions. We demonstrated a higher intensity of the MPN burdensome symptoms determined by the optimized self assessment MPN SAF TSS in patients with radiation associated, and in primary myelofibrosis patients, indica ting increased severity of patient's general conditions at the stage of diagnosis verification. It is advisable to use the optimized MPN SAF TSS at the moment of molecular genetic testing during the diagnosis of MPN for selection or modifying treatment strategies in order to achieve better quality of life for patients

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