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Macrophages promote anti-androgen resistance in prostate cancer bone disease

Xue-Feng Li1, Cigdem Selli1, Han-Lin Zhou2,3,4

  • 1Centre for Reproductive Health, College of Medicine and Veterinary Medicine, Queen's Medical Research Institute, The University of Edinburgh , Edinburgh, UK.

The Journal of Experimental Medicine
|February 7, 2023
PubMed

Insights

Macrophages drive resistance to prostate cancer treatments by activating specific signaling pathways. Inhibiting this pathway offers a new therapeutic strategy for metastatic castration-resistant prostate cancer.

Area of Science:

  • Oncology
  • Cancer Biology
  • Immunology

Background:

  • Metastatic castration-resistant prostate cancer (PC) is an advanced stage of PC resistant to androgen deprivation therapies (ADT).
  • The role of the tumor microenvironment, particularly macrophages, in driving ADT resistance is not well understood.
  • Bone metastasis is a common complication of advanced PC.

Purpose of the Study:

  • To investigate the contribution of the metastatic microenvironment to ADT resistance in prostate cancer.
  • To identify key cellular and molecular mechanisms underlying macrophage-mediated resistance.
  • To explore potential therapeutic strategies targeting this resistance mechanism.

Main Methods:

  • Utilized a novel in vivo model of bone-metastatic PC.
  • Analyzed patient transcriptomics datasets using bioinformatics.
  • Investigated the role of macrophages and the activin A/FN1/ITGA5/SRC signaling pathway.
  • Tested efficacy of macrophage depletion and SRC inhibition.

Main Results:

  • Macrophages are the predominant microenvironmental component in bone-metastatic PC.
  • Macrophages induce enzalutamide resistance via a wound-healing-like response and ECM-receptor gene expression.
  • Macrophage-derived activin A activates the FN1-ITGA5-SRC signaling cascade in PC cells, promoting resistance.
  • Macrophage depletion or SRC inhibition significantly suppressed resistant tumor growth.
  • Bioinformatics analysis supported the identified mechanism in patient data.

Conclusions:

  • Macrophages are critical drivers of anti-androgen resistance in metastatic prostate cancer.
  • The activin A-FN1-ITGA5-SRC signaling axis represents a novel mechanism of resistance.
  • Targeting macrophages or SRC signaling presents a promising therapeutic avenue for treating resistant metastatic PC.

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