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Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner

Oncogene volume 38, pages 716–730 (2019)Cite this article

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Abstract

Heterogeneous prostatic carcinoma-associated fibroblasts (CAF) contribute to tumor progression and resistance to androgen signaling deprivation therapy (ADT). CAF subjected to extended passaging, compared to low passage CAF, were found to lose tumor expansion potential and heterogeneity. Cell surface endoglin (CD105), known to be expressed on proliferative endothelia and mesenchymal stem cells, was diminished in high passage CAF. RNA-sequencing revealed SFRP1 to be distinctly expressed by tumor-inductive CAF, which was further demonstrated to occur in a CD105-dependent manner. Moreover, ADT resulted in further expansion of the CD105+ fibroblastic population and downstream SFRP1 in 3-dimensional cultures and patient-derived xenograft tissues. In patients, CD105+ fibroblasts were found to circumscribe epithelia with neuroendocrine differentiation. CAF-derived SFRP1, driven by CD105 signaling, was necessary and sufficient to induce prostate cancer neuroendocrine differentiation in a paracrine manner. A partially humanized CD105 neutralizing antibody, TRC105, inhibited fibroblastic SFRP1 expression and epithelial neuroendocrine differentiation. In a novel synthetic lethality paradigm, we found that simultaneously targeting the epithelia and its microenvironment with ADT and TRC105, respectively, reduced castrate-resistant tumor progression, in a model where either ADT or TRC105 alone had little effect.

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Acknowledgements

We thank Charles Theurer at Tracon Pharmaceuticals, Inc. for the TRC105 and M1043 neutralizing antibodies. The RNA-sequencing and histology slide scanning was performed at the Cedars-Sinai Genomics Core and Microscopy Core, respectively. This work was supported by grants from the National Cancer Institute (CA108646) and Veterans Affairs (BX001040) to NAB.

Author contributions

Conceptualization, MK, VRP-H, and NAB; Methodology and Project Administration, MK and VRP-H; Investigation, MK, VRP-H, AM, SH, KR-R, MT, RM, SB, BS, PA, FD, and BA; Formal analysis, DH, JZ; Writing, MK, VRP-H, and NAB; supervision and funding, NAB.

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  1. These authors contributed equally: Manabu Kato, Veronica R. Placencio-Hickok

Authors and Affiliations

  1. Nephro-Urologic Surgery and Andrology, Mie University Hospital, Tsu, Mie, Japan

    Manabu Kato

  2. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Veronica R. Placencio-Hickok, Anisha Madhav, Subhash Haldar, Manisha Tripathi, Sandrine Billet, Rajeev Mishra, Bethany Smith, Krizia Rohena-Rivera, Priyanka Agarwal, Frank Duong, Bryan Angara, David Hickok, Zhenqiu Liu & Neil A. Bhowmick

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Kato, M., Placencio-Hickok, V.R., Madhav, A. et al. Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner. Oncogene 38, 716–730 (2019). https://doi.org/10.1038/s41388-018-0461-3

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