Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

Navatha Shree Polavaram; Samikshan Dutta; Ridwan Islam; Arup K. Bag; Sohini Roy; David Poitz; Jeffrey Karnes; Lorenz C. Hofbauer; Manish Kohli; Brian A. Costello; Raffael Jimenez; Surinder K. Batra; Benjamin A. Teply; Michael H. Muders; Kaustubh Datta

doi:10.1038/s41413-021-00136-2

Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

Navatha Shree Polavaram, Samikshan Dutta, Ridwan Islam, Arup K. Bag, Sohini Roy, David Poitz, Jeffrey Karnes, Lorenz C. Hofbauer, Manish Kohli, Brian A. Costello, Raffael Jimenez, Surinder K. Batra, Benjamin A. Teply, Michael H. Muders, Kaustubh Datta

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

Original language	English (US)
Article number	24
Journal	Bone Research
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41413-021-00136-2
State	Published - Dec 2021

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Histology
Physiology

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@article{6a20b33a97d347369a644a8c6ce9d278,

title = "Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases",

abstract = "Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.",

author = "Polavaram, {Navatha Shree} and Samikshan Dutta and Ridwan Islam and Bag, {Arup K.} and Sohini Roy and David Poitz and Jeffrey Karnes and Hofbauer, {Lorenz C.} and Manish Kohli and Costello, {Brian A.} and Raffael Jimenez and Batra, {Surinder K.} and Teply, {Benjamin A.} and Muders, {Michael H.} and Kaustubh Datta",

note = "Funding Information: We thank Janice A. Taylor and James R. Talaska at the Confocal Laser Scanning Microscope Core Facility and UNMC tissue science facility at the University of Nebraska Medical Center (UNMC) for providing assistance and Dr. Rakesh Singh for use of Light microscopy. We also thank UNMC animal care facility for the mice maintenance and assistance. This work was supported by R01 CA 239343-01A1 (K.D.), RO1 CA 182435 (K.D.), Fred and Pamela Buffet cancer center pilot grant (K.D.; 2017 & 2018)R21CA241234-01 (S.D.), NE-DHHS-LB506 2020-21 (S.D.) DFG grant (L.C.H. and M.H.M.; project number: 27367690), The Rudolf-Becker-Foundation for translational prostate cancer research (M.H.M.), DFG Schwerpunktprogramm-2084 (L.C.H., µBONE), UO1 CA185148 (S.K.B.) and DOD PC170891 (S.K.B.). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41413-021-00136-2",

language = "English (US)",

volume = "9",

journal = "Bone Research",

issn = "2095-4700",

publisher = "Nature Publishing Group",

number = "1",

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T1 - Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

AU - Polavaram, Navatha Shree

AU - Dutta, Samikshan

AU - Islam, Ridwan

AU - Bag, Arup K.

AU - Roy, Sohini

AU - Poitz, David

AU - Karnes, Jeffrey

AU - Hofbauer, Lorenz C.

AU - Kohli, Manish

AU - Costello, Brian A.

AU - Jimenez, Raffael

AU - Batra, Surinder K.

AU - Teply, Benjamin A.

AU - Muders, Michael H.

AU - Datta, Kaustubh

N1 - Funding Information: We thank Janice A. Taylor and James R. Talaska at the Confocal Laser Scanning Microscope Core Facility and UNMC tissue science facility at the University of Nebraska Medical Center (UNMC) for providing assistance and Dr. Rakesh Singh for use of Light microscopy. We also thank UNMC animal care facility for the mice maintenance and assistance. This work was supported by R01 CA 239343-01A1 (K.D.), RO1 CA 182435 (K.D.), Fred and Pamela Buffet cancer center pilot grant (K.D.; 2017 & 2018)R21CA241234-01 (S.D.), NE-DHHS-LB506 2020-21 (S.D.) DFG grant (L.C.H. and M.H.M.; project number: 27367690), The Rudolf-Becker-Foundation for translational prostate cancer research (M.H.M.), DFG Schwerpunktprogramm-2084 (L.C.H., µBONE), UO1 CA185148 (S.K.B.) and DOD PC170891 (S.K.B.). Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

AB - Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

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DO - 10.1038/s41413-021-00136-2

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SN - 2095-4700

VL - 9

JO - Bone Research

JF - Bone Research

IS - 1

M1 - 24

ER -

Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

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