Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1.,Proceedings of the National Academy of Sciences of the United States of America

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Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1.
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2020-01-13 , DOI: 10.1073/pnas.1905384117
En-Chi Hsu _{1,

2} , Meghan A Rice _{1,

2} , Abel Bermudez _{1,

2} , Fernando Jose Garcia Marques _{1,

2} , Merve Aslan _{1,

2} , Shiqin Liu _{1,

2} , Ali Ghoochani _{1,

2} , Chiyuan Amy Zhang ₃ , Yun-Sheng Chen _{1,

2} , Aimen Zlitni _{1,

2} , Sahil Kumar ₄ , Rosalie Nolley ₃ , Frezghi Habte _{1,

2} , Michelle Shen _{1,

2} , Kashyap Koul _{1,

2} , Donna M Peehl ₅ , Amina Zoubeidi ₄ , Sanjiv S Gambhir _{1,

2,

6,

7,

8,

9} , Christian A Kunder ₁₀ , Sharon J Pitteri _{1,

2,

6} , James D Brooks _{2,

3,

6} , Tanya Stoyanova _{2,

6,

11}

Affiliation

Department of Radiology, Stanford University, Stanford, CA 94304.
Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA 94304.
Department of Urology, Stanford University, Stanford, CA 94304.
Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143.
Bio-X Program, Stanford University, Stanford, CA 94305.
Department of Bioengineering, Stanford University, Stanford, CA 94305.
Department of Materials Science & Engineering, Stanford University, Stanford, CA 94305.
Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305.
Department of Pathology, Stanford University, Stanford, CA 94304.
Department of Radiology, Stanford University, Stanford, CA 94304;

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.

中文翻译：

Trop2 通过 PARP1 驱动具有神经内分泌表型的转移性前列腺癌。

对雄激素剥夺疗法或去势抵抗性前列腺癌 (CRPC) 的耐药性通常伴有转移，目前是男性前列腺癌相关死亡的最终原因。最近，二次激素治疗导致神经内分泌前列腺癌 (NEPC) 的增加，这是 CRPC 的一种高度侵袭性变体。在这里，我们发现高水平的细胞表面受体 Trop2 可预测局部前列腺癌的复发。此外，Trop2 在 CRPC 和 NEPC 中显着升高，驱动前列腺癌生长，并诱导神经内分泌表型。Trop2 的过度表达会诱导肿瘤生长和转移，而 Trop2 的缺失会在体内抑制这些能力。Trop2 驱动的 NEPC 显示出 PARP1 的显着上调，和 PARP 抑制剂可显着延缓 Trop2 驱动的 NEPC 中的肿瘤生长和转移定植以及逆转神经内分泌特征。我们的研究结果将 Trop2 确定为具有神经内分泌表型的转移性前列腺癌的驱动因素和治疗靶标，并表明高 Trop2 水平可以识别对 Trop2 靶向治疗和 PARP1 抑制敏感的癌症。

更新日期：2020-01-29

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