Chemomechanically engineered 3D organotypic platforms of bladder cancer dormancy and reactivation

Taraka Sai Pavan Grandhi, Thrimoorthy Potta, Rajeshwar Nitiyanandan, Indrani Deshpande, Kaushal Rege

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Tumors undergo periods of dormancy followed by reactivation leading to metastatic disease. Arrest in the G0/G1 phase of the cell cycle and resistance to chemotherapeutic drugs are key hallmarks of dormant tumor cells. Here, we describe a 3D platform of bladder cancer cell dormancy and reactivation facilitated by a novel aminoglycoside-derived hydrogel, Amikagel. These 3D dormant tumor microenvironments (3D-DTMs) were arrested in the G0/G1 phase and were highly resistant to anti-proliferative drugs. Inhibition of targets in the cellular protein production machinery led to induction of endoplasmic reticulum (ER) stress and complete ablation of 3D-DTMs. Nanoparticle-mediated calcium delivery significantly accelerated ER stress-mediated 3D-DTM death. Transfer of 3D-DTMs onto weaker and adhesive Amikagels resulted in selective reactivation of a sub-population of N-cadherin deficient cells from dormancy. Whole-transcriptome analyses further indicated key biochemical differences between dormant and proliferative cancer cells. Taken together, our results indicate that 3D bladder cancer microenvironments of dormancy and reactivation can facilitate fundamental advances and novel drug discovery in cancer.

Original languageEnglish (US)
Pages (from-to)171-185
Number of pages15
JournalBiomaterials
Volume142
DOIs
StatePublished - Oct 1 2017

Keywords

  • 3D Tissue models
  • Cancer dormancy
  • Drug discovery
  • Reactivation

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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