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Somatic tissue engineering in mouse models reveals an actionable role for WNT pathway alterations in prostate cancer metastasis

ABSTRACT: Somatic tissue engineering in mouse models reveals an actionable role for WNT pathway alterations in prostate cancer metastasis

PROVIDER: PRJNA579352 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10341906.fastq.gz	Fastqsanger.gz
	SRR10341907.fastq.gz	Fastqsanger.gz
	SRR10341908.fastq.gz	Fastqsanger.gz
	SRR10341909.fastq.gz	Fastqsanger.gz
	SRR10341910.fastq.gz	Fastqsanger.gz

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Somatic tissue engineering in mouse models reveals an actionable role for WNT pathway alterations in prostate cancer metastasis

Project description:To study genetic factors that influence the progression and therapeutic response 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. Unexpectedly, a subset of particularly metastatic tumors acquired WNT pathway alterations, which are also associated with metastatic prostate cancer in humans. Harnessing features linked to the EPO-GEMM approach, we validate the WNT pathway as a key event in driving metastatic disease, a finding that we confirm in an orthogonal approach using mouse prostate organoids. Moreover, we show that tumors harboring WNT pathway alterations are sensitive to pharmacological WNT pathway inhibition. Thus, by leveraging the power of EPO-GEMMs, our studies reveal a functional role for WNT signaling in driving prostate cancer metastasis and validate the WNT pathway as an actionable therapeutic target in metastatic prostate cancer.

2020-04-28 | GSE139340 | GEO

Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis.

Project description: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 Trp53 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.This article is highlighted in the In This Issue feature, p. 890.

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Engineering nuclear elasticity to manipulate somatic cell fate

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Immuno-Transcriptomic Profiling Identifies Actionable Alterations in Pediatric Solid Malignancies

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Wnt inhibition facilitates RNA-mediated reprogramming of human somatic cells to naïve pluripotency

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NSD2 is an actionable driver of prostate cancer metastasis

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Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression during mitosis

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A feasibility study of returning clinically actionable somatic genomic alterations identified in a research laboratory.

Project description:PurposeMolecular profiling performed in the research setting usually does not benefit the patients that donate their tissues. Through a prospective protocol, we sought to determine the feasibility and utility of performing broad genomic testing in the research laboratory for discovery, and the utility of giving treating physicians access to research data, with the option of validating actionable alterations in the CLIA environment.Experimental design1200 patients with advanced cancer underwent characterization of their tumors with high depth hybrid capture sequencing of 201 genes in the research setting. Tumors were also tested in the CLIA laboratory, with a standardized hotspot mutation analysis on an 11, 46 or 50 gene platform.Results527 patients (44%) had at least one likely somatic mutation detected in an actionable gene using hotspot testing. With the 201 gene panel, 945 patients (79%) had at least one alteration in a potentially actionable gene that was undetected with the more limited CLIA panel testing. Sixty-four genomic alterations identified on the research panel were subsequently tested using an orthogonal CLIA assay. Of 16 mutations tested in the CLIA environment, 12 (75%) were confirmed. Twenty-five (52%) of 48 copy number alterations were confirmed. Nine (26.5%) of 34 patients with confirmed results received genotype-matched therapy. Seven of these patients were enrolled onto genotype-matched targeted therapy trials.ConclusionExpanded cancer gene sequencing identifies more actionable genomic alterations. The option of CLIA validating research results can provide alternative targets for personalized cancer therapy.

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