SPIN90 Depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression

Cancer Res. 2017 Sep 1;77(17):4710-4722. doi: 10.1158/0008-5472.CAN-17-0657. Epub 2017 Jun 26.

Abstract

Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here, we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients. Spin90 deficiency facilitated recruitment of mDia2 and APC complex to microtubules, resulting in increased microtubule acetylation. This increased acetylation promoted nuclear localization of YAP, which upregulated expression of myofibroblast marker genes on soft matrices. Spin90 depletion enhanced tumor progression, and blockade of microtubule acetylation in CAF significantly inhibited tumor growth in mice. Together, our data demonstrate that loss of SPIN90-mediated microtubule acetylation is a key step in CAF activation in low stiffness stroma. Moreover, correlation among these factors in human breast cancer tissue supports the clinical relevance of SPIN90 and microtubule acetylation in tumor development. Cancer Res; 77(17); 4710-22. ©2017 AACR.

MeSH terms

  • Acetylation
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Differentiation
  • Disease Progression
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microtubules / metabolism
  • Microtubules / pathology*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Nerve Tissue Proteins / physiology*
  • Phosphoproteins / metabolism
  • Stromal Cells / metabolism
  • Stromal Cells / pathology*
  • Transcription Factors
  • Tumor Cells, Cultured
  • Tumor Microenvironment
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Muscle Proteins
  • NCKIPSD protein, human
  • Nerve Tissue Proteins
  • Phosphoproteins
  • SPIN90 protein, mouse
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human