Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells

Francesca Andriani, Giulia Bertolini, Federica Facchinetti, Erika Baldoli, Massimo Moro, Patrizia Casalini, Roberto Caserini, Massimo Milione, Giorgia Leone, Giuseppe Pelosi, Ugo Pastorino, Gabriella Sozzi, Luca Roz

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Cancer cells within a tumor are functionally heterogeneous and specific subpopulations, defined as cancer initiating cells (CICs), are endowed with higher tumor forming potential. The CIC state, however, is not hierarchically stable and conversion of non-CICs to CICs under microenvironment signals might represent a determinant of tumor aggressiveness. How plasticity is regulated at the cellular level is however poorly understood. To identify determinants of plasticity in lung cancer we exposed eight different cell lines to TGFβ1 to induce EMT and stimulate modulation of CD133+ CICs. We show that response to TGFβ1 treatment is heterogeneous with some cells readily switching to stem cell state (1.5-2 fold CICs increase) and others being unresponsive to stimulation. This response is unrelated to original CICs content or extent of EMT engagement but is tightly dependent on balance between epithelial and mesenchymal features as measured by the ratio of expression of CDH1 (E-cadherin) to SNAI2. Epigenetic modulation of this balance can restore sensitivity of unresponsive models to microenvironmental stimuli, including those elicited by cancer-associated fibroblasts both in vitro and in vivo. In particular, tumors with increased prevalence of cells with features of partial EMT (hybrid epithelial/mesenchymal phenotype) are endowed with the highest plasticity and specific patterns of expression of SNAI2 and CDH1 markers identify a subset of tumors with worse prognosis. In conclusion, here we describe a connection between a hybrid epithelial/mesenchymal phenotype and conversion to stem-cell state in response to external stimuli. These findings have implications for current endeavors to identify tumors with increased plasticity.

Original languageEnglish
Pages (from-to)253-271
Number of pages19
JournalMolecular Oncology
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

Fingerprint

Cues
Lung Neoplasms
Stem Cells
Neoplasms
Phenotype
Cellular Microenvironment
Cadherins
Epigenomics
Cell Line

Keywords

  • Cancer initiating cells
  • CDH1
  • Lung cancer
  • Microenvironment
  • Plasticity
  • SNAI2

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells. / Andriani, Francesca; Bertolini, Giulia; Facchinetti, Federica; Baldoli, Erika; Moro, Massimo; Casalini, Patrizia; Caserini, Roberto; Milione, Massimo; Leone, Giorgia; Pelosi, Giuseppe; Pastorino, Ugo; Sozzi, Gabriella; Roz, Luca.

In: Molecular Oncology, Vol. 10, No. 2, 01.02.2016, p. 253-271.

Research output: Contribution to journalArticle

@article{0212d5ee715b4995bbe29493066ab728,
title = "Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells",
abstract = "Cancer cells within a tumor are functionally heterogeneous and specific subpopulations, defined as cancer initiating cells (CICs), are endowed with higher tumor forming potential. The CIC state, however, is not hierarchically stable and conversion of non-CICs to CICs under microenvironment signals might represent a determinant of tumor aggressiveness. How plasticity is regulated at the cellular level is however poorly understood. To identify determinants of plasticity in lung cancer we exposed eight different cell lines to TGFβ1 to induce EMT and stimulate modulation of CD133+ CICs. We show that response to TGFβ1 treatment is heterogeneous with some cells readily switching to stem cell state (1.5-2 fold CICs increase) and others being unresponsive to stimulation. This response is unrelated to original CICs content or extent of EMT engagement but is tightly dependent on balance between epithelial and mesenchymal features as measured by the ratio of expression of CDH1 (E-cadherin) to SNAI2. Epigenetic modulation of this balance can restore sensitivity of unresponsive models to microenvironmental stimuli, including those elicited by cancer-associated fibroblasts both in vitro and in vivo. In particular, tumors with increased prevalence of cells with features of partial EMT (hybrid epithelial/mesenchymal phenotype) are endowed with the highest plasticity and specific patterns of expression of SNAI2 and CDH1 markers identify a subset of tumors with worse prognosis. In conclusion, here we describe a connection between a hybrid epithelial/mesenchymal phenotype and conversion to stem-cell state in response to external stimuli. These findings have implications for current endeavors to identify tumors with increased plasticity.",
keywords = "Cancer initiating cells, CDH1, Lung cancer, Microenvironment, Plasticity, SNAI2",
author = "Francesca Andriani and Giulia Bertolini and Federica Facchinetti and Erika Baldoli and Massimo Moro and Patrizia Casalini and Roberto Caserini and Massimo Milione and Giorgia Leone and Giuseppe Pelosi and Ugo Pastorino and Gabriella Sozzi and Luca Roz",
year = "2016",
month = "2",
day = "1",
doi = "10.1016/j.molonc.2015.10.002",
language = "English",
volume = "10",
pages = "253--271",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells

AU - Andriani, Francesca

AU - Bertolini, Giulia

AU - Facchinetti, Federica

AU - Baldoli, Erika

AU - Moro, Massimo

AU - Casalini, Patrizia

AU - Caserini, Roberto

AU - Milione, Massimo

AU - Leone, Giorgia

AU - Pelosi, Giuseppe

AU - Pastorino, Ugo

AU - Sozzi, Gabriella

AU - Roz, Luca

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Cancer cells within a tumor are functionally heterogeneous and specific subpopulations, defined as cancer initiating cells (CICs), are endowed with higher tumor forming potential. The CIC state, however, is not hierarchically stable and conversion of non-CICs to CICs under microenvironment signals might represent a determinant of tumor aggressiveness. How plasticity is regulated at the cellular level is however poorly understood. To identify determinants of plasticity in lung cancer we exposed eight different cell lines to TGFβ1 to induce EMT and stimulate modulation of CD133+ CICs. We show that response to TGFβ1 treatment is heterogeneous with some cells readily switching to stem cell state (1.5-2 fold CICs increase) and others being unresponsive to stimulation. This response is unrelated to original CICs content or extent of EMT engagement but is tightly dependent on balance between epithelial and mesenchymal features as measured by the ratio of expression of CDH1 (E-cadherin) to SNAI2. Epigenetic modulation of this balance can restore sensitivity of unresponsive models to microenvironmental stimuli, including those elicited by cancer-associated fibroblasts both in vitro and in vivo. In particular, tumors with increased prevalence of cells with features of partial EMT (hybrid epithelial/mesenchymal phenotype) are endowed with the highest plasticity and specific patterns of expression of SNAI2 and CDH1 markers identify a subset of tumors with worse prognosis. In conclusion, here we describe a connection between a hybrid epithelial/mesenchymal phenotype and conversion to stem-cell state in response to external stimuli. These findings have implications for current endeavors to identify tumors with increased plasticity.

AB - Cancer cells within a tumor are functionally heterogeneous and specific subpopulations, defined as cancer initiating cells (CICs), are endowed with higher tumor forming potential. The CIC state, however, is not hierarchically stable and conversion of non-CICs to CICs under microenvironment signals might represent a determinant of tumor aggressiveness. How plasticity is regulated at the cellular level is however poorly understood. To identify determinants of plasticity in lung cancer we exposed eight different cell lines to TGFβ1 to induce EMT and stimulate modulation of CD133+ CICs. We show that response to TGFβ1 treatment is heterogeneous with some cells readily switching to stem cell state (1.5-2 fold CICs increase) and others being unresponsive to stimulation. This response is unrelated to original CICs content or extent of EMT engagement but is tightly dependent on balance between epithelial and mesenchymal features as measured by the ratio of expression of CDH1 (E-cadherin) to SNAI2. Epigenetic modulation of this balance can restore sensitivity of unresponsive models to microenvironmental stimuli, including those elicited by cancer-associated fibroblasts both in vitro and in vivo. In particular, tumors with increased prevalence of cells with features of partial EMT (hybrid epithelial/mesenchymal phenotype) are endowed with the highest plasticity and specific patterns of expression of SNAI2 and CDH1 markers identify a subset of tumors with worse prognosis. In conclusion, here we describe a connection between a hybrid epithelial/mesenchymal phenotype and conversion to stem-cell state in response to external stimuli. These findings have implications for current endeavors to identify tumors with increased plasticity.

KW - Cancer initiating cells

KW - CDH1

KW - Lung cancer

KW - Microenvironment

KW - Plasticity

KW - SNAI2

UR - http://www.scopus.com/inward/record.url?scp=84958899570&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958899570&partnerID=8YFLogxK

U2 - 10.1016/j.molonc.2015.10.002

DO - 10.1016/j.molonc.2015.10.002

M3 - Article

VL - 10

SP - 253

EP - 271

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 2

ER -