In the footsteps of migrating cancer cells

Dissertation

Anja Mai

Research output: ThesisDissertationCollection of Articles

Abstract

The capability of cells to migrate is vital for many physiological processes, including embryogenesis, tissue repair, and immune surveillance. However, cell migration becomes fatal when cancer cells acquire invasive properties and set out to conquer new metastatic niches in the body. In fact, metastasis is the major cause for cancer mortality. Thus, in order to selectively fight metastasising tumour cells, without harming migrating host cells, it is of great importance to understand the molecular machineries that orchestrate cell motility under different circumstances. In the course of this thesis, we have unveiled conceptually new mechanisms that account for cancer cell migration in 2D and 3D matrix environments. We first discovered a novel function for p120RasGAP in the control of integrin recycling. Integrins are transmembrane receptors that crucially balance cell adhesion and migration. Their function is carefully regulated by ECM ligand-binding activity, but also by their targeted trafficking from and to the plasma membrane. We discovered a non-catalytic, competitive mechanism by which p120RasGAP replaces the endocytic Rab21 from the integrin cargo on early endosomes, which subsequently allows the αβ1-heterodimer to recycle back to the plasma membrane. Besides the continuous traffic of integrins, also their localisation needs to be directed to dynamic sites of adhesion. We found that in metastasising lung cancer cells, the loss of
intercellular contacts contributes to increased cell motility by the PKCε-dependent complex formation between the tight junction protein ZO-1 and α5β1-integrin. This complex localises to the leading edge, where it maintains the lamellipodium and supports local Rac1 activation. Thereby, the α5β1–ZO-1 duo promotes directionally persistent migration and may hence fuel the metastatic dissemination of various human tumour cells. Finally, we shed light on the invasive switch induced by oncogenic c-Met signalling. The growth factor receptor is implicated in the progression of most carcinomas to metastatic
disease. In this study, we identified novel c-Met effectors: RhoA, which promotes phenotypic alterations, and Hip1, which mediates c-Met–stimulated α1-integrin endocytosis. Moreover, we found that c-Met triggers tumour cell migration in 3D matrices with distinct invasion modes, depending on the mechanism of receptor activation. Collectively, these findings provide new information on the complex molecular networks that drive cancer cell migration and invasion. As research progresses, increasing knowledge will help us to eventually design potent therapies to combat disseminating tumours.
Original languageEnglish
QualificationDoctor Degree
Awarding Institution
  • University of Turku
Supervisors/Advisors
  • Ivaska, Johanna, Supervisor, External person
Place of PublicationTurku
Publisher
Print ISBNs978-951-29-4806-2
Electronic ISBNs978-951-29-4807-9
Publication statusPublished - 2011
MoE publication typeG5 Doctoral dissertation (article)

Fingerprint

Cell Movement
Integrins
p120 GTPase Activating Protein
Neoplasms
Zonula Occludens-1 Protein
Cell Membrane
Physiological Phenomena
Pseudopodia
Endosomes
Recycling
Endocytosis
Cell Adhesion
Embryonic Development
Lung Neoplasms
Neoplasm Metastasis
Ligands
Carcinoma
Mortality
Research

Keywords

  • Cell migration
  • integrin
  • trafficking
  • c-Met
  • metastasis
  • ZO-1

Cite this

Mai, A. (2011). In the footsteps of migrating cancer cells: Dissertation. Turku: University of Turku.
Mai, Anja. / In the footsteps of migrating cancer cells : Dissertation. Turku : University of Turku, 2011. 84 p.
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Mai, A 2011, 'In the footsteps of migrating cancer cells: Dissertation', Doctor Degree, University of Turku, Turku.

In the footsteps of migrating cancer cells : Dissertation. / Mai, Anja.

Turku : University of Turku, 2011. 84 p.

Research output: ThesisDissertationCollection of Articles

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N2 - The capability of cells to migrate is vital for many physiological processes, including embryogenesis, tissue repair, and immune surveillance. However, cell migration becomes fatal when cancer cells acquire invasive properties and set out to conquer new metastatic niches in the body. In fact, metastasis is the major cause for cancer mortality. Thus, in order to selectively fight metastasising tumour cells, without harming migrating host cells, it is of great importance to understand the molecular machineries that orchestrate cell motility under different circumstances. In the course of this thesis, we have unveiled conceptually new mechanisms that account for cancer cell migration in 2D and 3D matrix environments. We first discovered a novel function for p120RasGAP in the control of integrin recycling. Integrins are transmembrane receptors that crucially balance cell adhesion and migration. Their function is carefully regulated by ECM ligand-binding activity, but also by their targeted trafficking from and to the plasma membrane. We discovered a non-catalytic, competitive mechanism by which p120RasGAP replaces the endocytic Rab21 from the integrin cargo on early endosomes, which subsequently allows the αβ1-heterodimer to recycle back to the plasma membrane. Besides the continuous traffic of integrins, also their localisation needs to be directed to dynamic sites of adhesion. We found that in metastasising lung cancer cells, the loss ofintercellular contacts contributes to increased cell motility by the PKCε-dependent complex formation between the tight junction protein ZO-1 and α5β1-integrin. This complex localises to the leading edge, where it maintains the lamellipodium and supports local Rac1 activation. Thereby, the α5β1–ZO-1 duo promotes directionally persistent migration and may hence fuel the metastatic dissemination of various human tumour cells. Finally, we shed light on the invasive switch induced by oncogenic c-Met signalling. The growth factor receptor is implicated in the progression of most carcinomas to metastaticdisease. In this study, we identified novel c-Met effectors: RhoA, which promotes phenotypic alterations, and Hip1, which mediates c-Met–stimulated α1-integrin endocytosis. Moreover, we found that c-Met triggers tumour cell migration in 3D matrices with distinct invasion modes, depending on the mechanism of receptor activation. Collectively, these findings provide new information on the complex molecular networks that drive cancer cell migration and invasion. As research progresses, increasing knowledge will help us to eventually design potent therapies to combat disseminating tumours.

AB - The capability of cells to migrate is vital for many physiological processes, including embryogenesis, tissue repair, and immune surveillance. However, cell migration becomes fatal when cancer cells acquire invasive properties and set out to conquer new metastatic niches in the body. In fact, metastasis is the major cause for cancer mortality. Thus, in order to selectively fight metastasising tumour cells, without harming migrating host cells, it is of great importance to understand the molecular machineries that orchestrate cell motility under different circumstances. In the course of this thesis, we have unveiled conceptually new mechanisms that account for cancer cell migration in 2D and 3D matrix environments. We first discovered a novel function for p120RasGAP in the control of integrin recycling. Integrins are transmembrane receptors that crucially balance cell adhesion and migration. Their function is carefully regulated by ECM ligand-binding activity, but also by their targeted trafficking from and to the plasma membrane. We discovered a non-catalytic, competitive mechanism by which p120RasGAP replaces the endocytic Rab21 from the integrin cargo on early endosomes, which subsequently allows the αβ1-heterodimer to recycle back to the plasma membrane. Besides the continuous traffic of integrins, also their localisation needs to be directed to dynamic sites of adhesion. We found that in metastasising lung cancer cells, the loss ofintercellular contacts contributes to increased cell motility by the PKCε-dependent complex formation between the tight junction protein ZO-1 and α5β1-integrin. This complex localises to the leading edge, where it maintains the lamellipodium and supports local Rac1 activation. Thereby, the α5β1–ZO-1 duo promotes directionally persistent migration and may hence fuel the metastatic dissemination of various human tumour cells. Finally, we shed light on the invasive switch induced by oncogenic c-Met signalling. The growth factor receptor is implicated in the progression of most carcinomas to metastaticdisease. In this study, we identified novel c-Met effectors: RhoA, which promotes phenotypic alterations, and Hip1, which mediates c-Met–stimulated α1-integrin endocytosis. Moreover, we found that c-Met triggers tumour cell migration in 3D matrices with distinct invasion modes, depending on the mechanism of receptor activation. Collectively, these findings provide new information on the complex molecular networks that drive cancer cell migration and invasion. As research progresses, increasing knowledge will help us to eventually design potent therapies to combat disseminating tumours.

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KW - integrin

KW - trafficking

KW - c-Met

KW - metastasis

KW - ZO-1

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SN - 978-951-29-4806-2

T3 - Annales Universitatis Turkuensis: A I Astronomica - Chemica - Physica - Mathematica

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Mai A. In the footsteps of migrating cancer cells: Dissertation. Turku: University of Turku, 2011. 84 p.