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

Manabu Kato, 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

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)716-730
Number of pages15
JournalOncogene
Volume38
Issue number5
DOIs
StatePublished - Jan 31 2019

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Kato, M., Placencio-Hickok, V. R., Madhav, A., Haldar, S., Tripathi, M., Billet, S., Mishra, R., Smith, B., Rohena-Rivera, K., Agarwal, P., Duong, F., Angara, B., Hickok, D., Liu, Z., & Bhowmick, N. A. (2019). Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner. Oncogene, 38(5), 716-730. https://doi.org/10.1038/s41388-018-0461-3