To study genetic factors influencing the progression and therapeutic responses of advanced prostate cancer, we developed a fast and flexible system that introduces genetic alterations relevant to human disease directly into the prostate glands of mice using tissue electroporation. These electroporation-based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional germline models and, by modeling genetic factors linked to late-stage human disease, can produce tumors that are metastatic and castration-resistant. A subset of tumors with alterations acquired spontaneous WNT pathway alterations, which are also associated with metastatic prostate cancer in humans. Using the EPO-GEMM approach and an orthogonal organoid-based model, we show that WNT pathway activation drives metastatic disease that is sensitive to pharmacologic WNT pathway inhibition. Thus, by leveraging EPO-GEMMs, we reveal a functional role for WNT signaling in driving prostate cancer metastasis and validate the WNT pathway as therapeutic target in metastatic prostate cancer. SIGNIFICANCE: Our understanding of the factors driving metastatic prostate cancer is limited by the paucity of models of late-stage disease. Here, we develop EPO-GEMMs of prostate cancer and use them to identify and validate the WNT pathway as an actionable driver of aggressive metastatic disease..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1242 | DOI Listing |
Cell Rep
December 2024
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address:
Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in castration-resistant prostate cancer, but the extent to which they drive AR activity is unclear. We generated a subline of VCaP cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ). AR activity in VCaP16 is driven by ARv7, independently of full-length AR (ARfl), and its cistrome and transcriptome mirror those of ARfl in VCaP cells.
View Article and Find Full Text PDFDiscov Oncol
December 2024
Department of Radiotherapy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China.
High expression of immune checkpoint molecule B7-H3 (CD276) in many cancer types makes it a promising immunotherapeutic target. Both coinhibitory and costimulatory effects of B7-H3 in tumors have been demonstrated, but the mechanism of B7-H3 immune response under dual effects is open to question. B7-H3 is crucially involved in the migration and invasion, angiogenesis, metabolism and chemotherapy resistance of prostate cancer.
View Article and Find Full Text PDFBackground: Previous observational studies examining the relationship between cadmium exposure and various cancers have yielded conflicting results. This study aims to comprehensively clarify the relationship between blood cadmium concentration (BCC) and nine specific cancers.
Methods: A retrospective analysis of National Health and Nutrition Examination Survey (NHANES) 1999-2018 identified 36,991 participants.
Prostate
December 2024
Urology Unit, Department of Medical, Oral and Biotechnological Sciences, 'G. d'Annunzio University', Chieti, Italy.
Introduction: The introduction of multiparametric prostate magnetic resonance imaging (mpMRI) has revolutionized prostate cancer (PCa) diagnosis, enhancing the localization of clinically significant prostate cancer (csPCa) and guiding targeted biopsies. However, significant disparities in the execution, interpretation, and reporting of prostate MRI examinations across centers necessitate greater standardization and accuracy. This study compares the diagnostic efficacy of mpMRI from academic and nonacademic centers in detecting csPCa and identifies factors associated with csPCa detection.
View Article and Find Full Text PDFProstate
December 2024
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
Introduction: Non-castrating therapies are an unmet clinical need for patients with advanced prostate cancer. To maximize quality of life and prioritize cardiovascular health, we investigated SGLT2 inhibitors as a non-castrating therapy in patients with prostate cancer.
Materials And Methods: We conducted a retrospective analysis of patients with either local or biochemically recurrent prostate cancer who initiated therapy with an SGLT2 inhibitor without concurrent androgen deprivation therapy.
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