Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1

En-Chi Hsu; Meghan A Rice; Abel Bermudez; Fernando Jose Garcia Marques; Merve Aslan; Shiqin Liu; Ali Ghoochani; Chiyuan Amy Zhang; Yun-Sheng Chen; Aimen Zlitni; Sahil Kumar; Rosalie Nolley; Frezghi Habte; Michelle Shen; Kashyap Koul; Donna M Peehl; Amina Zoubeidi; Sanjiv S Gambhir; Christian A Kunder; Sharon J Pitteri; James D Brooks; Tanya Stoyanova

doi:10.1073/pnas.1905384117

Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1

Proc Natl Acad Sci U S A. 2020 Jan 28;117(4):2032-2042. doi: 10.1073/pnas.1905384117. Epub 2020 Jan 13.

Authors

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 Zhang³, Yun-Sheng Chen^{1

2}, Aimen Zlitni^{1

2}, Sahil Kumar⁴, Rosalie Nolley³, Frezghi Habte^{1

2}, Michelle Shen^{1

2}, Kashyap Koul^{1

2}, Donna M Peehl⁵, Amina Zoubeidi⁴, Sanjiv S Gambhir^{1

2

6

7

8

9}, Christian A Kunder¹⁰, Sharon J Pitteri^{1

2

6}, James D Brooks^{2

3

6}, Tanya Stoyanova^{11

2

6}

Affiliations

¹ Department of Radiology, Stanford University, Stanford, CA 94304.
² Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA 94304.
³ Department of Urology, Stanford University, Stanford, CA 94304.
⁴ Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
⁵ Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143.
⁶ Bio-X Program, Stanford University, Stanford, CA 94305.
⁷ Department of Bioengineering, Stanford University, Stanford, CA 94305.
⁸ Department of Materials Science & Engineering, Stanford University, Stanford, CA 94305.
⁹ Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305.
¹⁰ Department of Pathology, Stanford University, Stanford, CA 94304.
¹¹ Department of Radiology, Stanford University, Stanford, CA 94304; stanya@stanford.edu.

Abstract

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.

Keywords: NEPC; Trop2; cancer; prostate.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism*
Apoptosis
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Bone Neoplasms / drug therapy
Bone Neoplasms / metabolism
Bone Neoplasms / secondary*
Carcinoma, Neuroendocrine / drug therapy
Carcinoma, Neuroendocrine / metabolism
Carcinoma, Neuroendocrine / pathology*
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism*
Cell Movement
Cell Proliferation
Follow-Up Studies
Gene Expression Regulation, Neoplastic*
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Invasiveness
Phenotype
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 / genetics
Poly (ADP-Ribose) Polymerase-1 / metabolism*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Prognosis
Prostatic Neoplasms, Castration-Resistant / drug therapy
Prostatic Neoplasms, Castration-Resistant / metabolism
Prostatic Neoplasms, Castration-Resistant / pathology*
Survival Rate
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Antigens, Neoplasm
Biomarkers, Tumor
Cell Adhesion Molecules
Poly(ADP-ribose) Polymerase Inhibitors
TACSTD2 protein, human
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding