Cellular cartography reveals mouse prostate organization and determinants of castration resistance.

Inadequate response to androgen deprivation therapy (ADT) frequently arises in prostate cancer, driven by cellular mechanisms that remain poorly understood. Here, we integrated single-cell RNA sequencing, single-cell multiomics, and spatial transcriptomics to define the transcriptional, epigenetic, and spatial basis of cell identity and castration response in the mouse prostate. Leveraging these data along with a meta-analysis of human prostates and prostate cancer, we identified cellular orthologs and key determinants of ADT response and resistance.

Molecular characterization of archival adrenal tumor tissue from patients with ACTH-independent Cushing syndrome.

Cushing syndrome represents a multitude of signs and symptoms associated with long-term and excessive exposure to glucocorticoids. Solitary cortisol-producing adenomas (CPAs) account for most cases of ACTH-independent Cushing syndrome (CS). Technological advances in next-generation sequencing have significantly increased our understanding about the genetic landscape of CPAs.

Germline loss-of-function variant in the E3 ubiquitin ligase TRAF2 in a young adult patient with medulloblastoma: a case report.

We identified a rare heterozygous germline loss-of-function variant in the tumor necrosis factor receptor-associated factor 2 (TRAF2) in a young adult patient diagnosed with medulloblastoma. This variant is located within the TRAF-C domain of the E3 ubiquitin ligase protein and is predicted to diminish the binding affinity of TRAF2 to upstream receptors and associated adaptor proteins. Integrative genomics revealed a biallelic loss of TRAF2 via partial copy-neutral loss-of-heterozygosity of 9q in the medulloblastoma genome.

Spatial Transcriptomic Profiling to Characterize the Nature of Peripheral- Versus Transition-zone Prostate Cancer.

Background And Objective: Prostate cancer (PC) in the transition zone (TZ) has better prognosis than peripheral-zone (PZ) PC despite higher prostate-specific antigen (PSA) in patients with TZ tumors. Our aim was to characterize molecular differences between TZ and PZ tumors and their clinical implications.

Methods: We performed spatial whole-transcriptome analyses of 50 regions of interest (ROIs) from three patients with PZ and/or TZ PC.

Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab in patients with metastatic castration-resistant prostate cancer.

Increasing the response rates of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) presents a significant challenge. ESK981 is a multi-tyrosine kinase and PIKfyve lipid kinase inhibitor that augments immunotherapeutic responses. In this phase II study, ESK981 was combined with the PD-1 blocking monoclonal antibody nivolumab to test for potentially improved response rates in patients with mCRPC who have progressed on androgen receptor (AR)-targeted agents and chemotherapy.

Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader.

Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast cancer (TNBC) and other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders of CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery of as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader.

Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition.

Cyclin-dependent kinases 12/13 play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Biallelic CDK12 loss has been documented in various malignancies. Here, we develop a selective CDK12/13 PROTAC degrader, YJ9069, which effectively inhibits proliferation in subsets of prostate cancer cells preferentially over benign immortalized cells.

Incidental testicular germ cell tumor in a transgender woman: A case report.

Testicular cancer found incidentally during gender-affirming orchiectomy is infrequently reported in the literature. This report details a 27-year-old transgender woman whose testicular cancer was discovered incidentally upon routine histopathologic examination of the orchiectomy specimen. The patient did not present with any clinical signs of malignancy.

Phase II trial of multi-kinase inhibitor ESK981 in patients with metastatic castration-resistant prostate cancer.

ESK981 is a potent tyrosine kinase and PIKfyve lipid kinase inhibitor. This phase II trial evaluated the efficacy of ESK981 as a single agent in patients with androgen receptor-positive (AR +) metastatic castration-resistant prostate cancer (mCRPC). Eligible patients had mCRPC with progression on AR-targeted agents and without prior chemotherapy treatment.

PLXNA1 confers enzalutamide resistance in prostate cancer via AKT signaling pathway.

Although targeting the androgen signaling pathway by androgen receptor (AR) inhibitors, including enzalutamide, has shown therapeutic effectiveness, inevitable emergence of acquired resistance remains a critical challenge in the treatment of advanced prostate cancer (PCa). Recognizing targetable genomic aberrations that trigger endocrine treatment failure holds great promise for advancing therapeutic interventions. Here, we characterized PLXNA1, amplified in a subset of PCa patients, as a contributor to enzalutamide resistance (ENZR).

Circular RNA in cancer.

Over the past decade, circular RNA (circRNA) research has evolved into a bona fide research field shedding light on the functional consequence of this unique family of RNA molecules in cancer. Although the method of formation and the abundance of circRNAs can differ from their cognate linear mRNA, the spectrum of interacting partners and their resultant cellular functions in oncogenesis are analogous. However, with 10 times more diversity in circRNA variants compared with linear RNA variants, combined with their hyperstability in the cell, circRNAs are equipped to influence every stage of oncogenesis.

A systematic overview of single-cell transcriptomics databases, their use cases, and limitations.

Rapid advancements in high-throughput single-cell RNA-seq (scRNA-seq) technologies and experimental protocols have led to the generation of vast amounts of transcriptomic data that populates several online databases and repositories. Here, we systematically examined large-scale scRNA-seq databases, categorizing them based on their scope and purpose such as general, tissue-specific databases, disease-specific databases, cancer-focused databases, and cell type-focused databases. Next, we discuss the technical and methodological challenges associated with curating large-scale scRNA-seq databases, along with current computational solutions.

PARP inhibitor therapy in patients with IDH1 mutated cholangiocarcinoma.

Background: Isocitrate dehydrogenase 1 (IDH1) missense mutations occur at a frequency of 10%-15% in intrahepatic cholangiocarcinoma (iCCA). IDH1 mutations result in accumulation of (R)-2-hydroxyglutarate, an oncometabolite that leads to DNA hypermethylation and impairment of homologous recombination (HR). Impairment of HR results in a "BRCAness" phenotype which may confer sensitivity to poly(ADP ribose) polymerase (PARP) inhibition.

Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies.

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling.

Renal epithelioid angiomyolipomas overexpress TFE3 and the TFE3-regulated gene TRIM63 in the absence of TFE3 rearrangement.

Angiomyolipoma (AML) is a neoplasm within the perivascular epithelioid cell tumor family that occurs somewhat frequently in the kidney. Most are indolent and discovered incidentally, with rare tumors demonstrating malignant clinical behavior. A small subset of renal AMLs with epithelioid features are associated with aggressive behavior, and may demonstrate morphologic overlap with renal cell carcinomas (e.

Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.

Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models.

PIKfyve, expressed by CD11c-positive cells, controls tumor immunity.

Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy.