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Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer [VCaP_EnzaResistant_9817-HYW]

ABSTRACT: Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer [VCaP_EnzaResistant_9817-HYW]

PROVIDER: PRJNA1133011 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR29760735_1.fastq.gz	Fastqsanger.gz
	SRR29760735_2.fastq.gz	Fastqsanger.gz
	SRR29760738_1.fastq.gz	Fastqsanger.gz
	SRR29760738_2.fastq.gz	Fastqsanger.gz

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Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer

Project description:Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identify a novel paracrine mechanism in which CAF-secreted asporin (ASPN) activates ErbB signaling and subsequent migration of adjacent metastatic prostate cancer cells. Our data support that ASPN binds directly to HER3 to induce HER2/HER3 heterodimerization and activation of the PI3-kinase and MAP-kinase pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Small molecule and antibody-drug conjugates targeting HER2/HER3 demonstrated efficacy in vitro, with near complete resolution of tumors in vivo. Clinically, over 50% of human prostate cancer metastases show expression of HER2/HER3, along with ASPN expressing CAF. Collectively, these findings support ASPN functions as a HER3 ligand to induce cellular migration which can be targeted with anti-HER2/HER3 therapies, highlighting the potential clinical benefit for patients with metastatic prostate cancer.

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