Automated tracking of tumor-stroma morphology in microtissues identifies functional targets within the tumor microenvironment for therapeutic intervention

Malin Åkerfelt, Neslihan Bayramoglu, Sean Robinson, Mervi Toriseva, Hannu-Pekka Schukov, Ville Härmä, Johannes Virtanen, Raija Sormunen, Mika Kaakinen, Juho Kannala, Lauri Eklund, Janne Heikkilä, Matthias Nees (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

15 Citations (Scopus)

Abstract

Cancer-associated fibroblasts (CAFs) constitute an important part of the tumor microenvironment and promote invasion via paracrine functions and physical impact on the tumor. Although the importance of including CAFs into three-dimensional (3D) cell cultures has been acknowledged, computational support for quantitative live-cell measurements of complex cell cultures has been lacking. Here, we have developed a novel automated pipeline to model tumor-stroma interplay, track motility and quantify morphological changes of 3D co-cultures, in real-time live-cell settings. The platform consists of microtissues from prostate cancer cells, combined with CAFs in extracellular matrix that allows biochemical perturbation. Tracking of fibroblast dynamics revealed that CAFs guided the way for tumor cells to invade and increased the growth and invasiveness of tumor organoids. We utilized the platform to determine the efficacy of inhibitors in prostate cancer and the associated tumor microenvironment as a functional unit. Interestingly, certain inhibitors selectively disrupted tumor-CAF interactions, e.g. focal adhesion kinase (FAK) inhibitors specifically blocked tumor growth and invasion concurrently with fibroblast spreading and motility. This complex phenotype was not detected in other standard in vitro models. These results highlight the advantage of our approach, which recapitulates tumor histology and can significantly improve cancer target validation in vitro.
Original languageEnglish
Pages (from-to)30035-30056
JournalOncotarget
Volume6
Issue number30
DOIs
Publication statusPublished - 2015
MoE publication typeA1 Journal article-refereed

Fingerprint

Tumor Microenvironment
Neoplasms
Therapeutics
Prostatic Neoplasms
Cell Culture Techniques
Fibroblasts
Organoids
Focal Adhesion Protein-Tyrosine Kinases
Growth
Coculture Techniques
Extracellular Matrix
Cancer-Associated Fibroblasts
Histology
Phenotype

Keywords

  • 3D co-culture
  • cancer associated fibroblast (CAF)
  • focal adhesion kinase (FAK)
  • invasion
  • phenotypic screening

Cite this

Åkerfelt, Malin ; Bayramoglu, Neslihan ; Robinson, Sean ; Toriseva, Mervi ; Schukov, Hannu-Pekka ; Härmä, Ville ; Virtanen, Johannes ; Sormunen, Raija ; Kaakinen, Mika ; Kannala, Juho ; Eklund, Lauri ; Heikkilä, Janne ; Nees, Matthias. / Automated tracking of tumor-stroma morphology in microtissues identifies functional targets within the tumor microenvironment for therapeutic intervention. In: Oncotarget. 2015 ; Vol. 6, No. 30. pp. 30035-30056.
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abstract = "Cancer-associated fibroblasts (CAFs) constitute an important part of the tumor microenvironment and promote invasion via paracrine functions and physical impact on the tumor. Although the importance of including CAFs into three-dimensional (3D) cell cultures has been acknowledged, computational support for quantitative live-cell measurements of complex cell cultures has been lacking. Here, we have developed a novel automated pipeline to model tumor-stroma interplay, track motility and quantify morphological changes of 3D co-cultures, in real-time live-cell settings. The platform consists of microtissues from prostate cancer cells, combined with CAFs in extracellular matrix that allows biochemical perturbation. Tracking of fibroblast dynamics revealed that CAFs guided the way for tumor cells to invade and increased the growth and invasiveness of tumor organoids. We utilized the platform to determine the efficacy of inhibitors in prostate cancer and the associated tumor microenvironment as a functional unit. Interestingly, certain inhibitors selectively disrupted tumor-CAF interactions, e.g. focal adhesion kinase (FAK) inhibitors specifically blocked tumor growth and invasion concurrently with fibroblast spreading and motility. This complex phenotype was not detected in other standard in vitro models. These results highlight the advantage of our approach, which recapitulates tumor histology and can significantly improve cancer target validation in vitro.",
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Åkerfelt, M, Bayramoglu, N, Robinson, S, Toriseva, M, Schukov, H-P, Härmä, V, Virtanen, J, Sormunen, R, Kaakinen, M, Kannala, J, Eklund, L, Heikkilä, J & Nees, M 2015, 'Automated tracking of tumor-stroma morphology in microtissues identifies functional targets within the tumor microenvironment for therapeutic intervention', Oncotarget, vol. 6, no. 30, pp. 30035-30056. https://doi.org/10.18632/oncotarget.5046

Automated tracking of tumor-stroma morphology in microtissues identifies functional targets within the tumor microenvironment for therapeutic intervention. / Åkerfelt, Malin; Bayramoglu, Neslihan; Robinson, Sean; Toriseva, Mervi; Schukov, Hannu-Pekka; Härmä, Ville; Virtanen, Johannes; Sormunen, Raija; Kaakinen, Mika; Kannala, Juho; Eklund, Lauri; Heikkilä, Janne; Nees, Matthias (Corresponding Author).

In: Oncotarget, Vol. 6, No. 30, 2015, p. 30035-30056.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Automated tracking of tumor-stroma morphology in microtissues identifies functional targets within the tumor microenvironment for therapeutic intervention

AU - Åkerfelt, Malin

AU - Bayramoglu, Neslihan

AU - Robinson, Sean

AU - Toriseva, Mervi

AU - Schukov, Hannu-Pekka

AU - Härmä, Ville

AU - Virtanen, Johannes

AU - Sormunen, Raija

AU - Kaakinen, Mika

AU - Kannala, Juho

AU - Eklund, Lauri

AU - Heikkilä, Janne

AU - Nees, Matthias

PY - 2015

Y1 - 2015

N2 - Cancer-associated fibroblasts (CAFs) constitute an important part of the tumor microenvironment and promote invasion via paracrine functions and physical impact on the tumor. Although the importance of including CAFs into three-dimensional (3D) cell cultures has been acknowledged, computational support for quantitative live-cell measurements of complex cell cultures has been lacking. Here, we have developed a novel automated pipeline to model tumor-stroma interplay, track motility and quantify morphological changes of 3D co-cultures, in real-time live-cell settings. The platform consists of microtissues from prostate cancer cells, combined with CAFs in extracellular matrix that allows biochemical perturbation. Tracking of fibroblast dynamics revealed that CAFs guided the way for tumor cells to invade and increased the growth and invasiveness of tumor organoids. We utilized the platform to determine the efficacy of inhibitors in prostate cancer and the associated tumor microenvironment as a functional unit. Interestingly, certain inhibitors selectively disrupted tumor-CAF interactions, e.g. focal adhesion kinase (FAK) inhibitors specifically blocked tumor growth and invasion concurrently with fibroblast spreading and motility. This complex phenotype was not detected in other standard in vitro models. These results highlight the advantage of our approach, which recapitulates tumor histology and can significantly improve cancer target validation in vitro.

AB - Cancer-associated fibroblasts (CAFs) constitute an important part of the tumor microenvironment and promote invasion via paracrine functions and physical impact on the tumor. Although the importance of including CAFs into three-dimensional (3D) cell cultures has been acknowledged, computational support for quantitative live-cell measurements of complex cell cultures has been lacking. Here, we have developed a novel automated pipeline to model tumor-stroma interplay, track motility and quantify morphological changes of 3D co-cultures, in real-time live-cell settings. The platform consists of microtissues from prostate cancer cells, combined with CAFs in extracellular matrix that allows biochemical perturbation. Tracking of fibroblast dynamics revealed that CAFs guided the way for tumor cells to invade and increased the growth and invasiveness of tumor organoids. We utilized the platform to determine the efficacy of inhibitors in prostate cancer and the associated tumor microenvironment as a functional unit. Interestingly, certain inhibitors selectively disrupted tumor-CAF interactions, e.g. focal adhesion kinase (FAK) inhibitors specifically blocked tumor growth and invasion concurrently with fibroblast spreading and motility. This complex phenotype was not detected in other standard in vitro models. These results highlight the advantage of our approach, which recapitulates tumor histology and can significantly improve cancer target validation in vitro.

KW - 3D co-culture

KW - cancer associated fibroblast (CAF)

KW - focal adhesion kinase (FAK)

KW - invasion

KW - phenotypic screening

U2 - 10.18632/oncotarget.5046

DO - 10.18632/oncotarget.5046

M3 - Article

VL - 6

SP - 30035

EP - 30056

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 30

ER -