Studying the functional relevance of lung cancer genetic drivers in their physiological niche

Forskningsoutput: AvhandlingDoktorsavhandlingSamling av artiklar

Sammanfattning

Lung cancer is the leading cause of cancer related deaths worldwide. It is characterised with a high level of intra- and intertumour heterogeneity. Large lung cancer sequencing efforts have identified clear histopathology-specific genetic alteration patterns, which in the cases of lung adenocarcinomas are applied in clinics to direct treatment. Furthermore, lung cancer immunotherapy approaches have recently shown promising results in clinical trials. However, a deeper understanding of the functional importance of novel lung cancer genes as well as the lung cancer-related niche and cell type specific propensities leading to molecular and microenvironmental tumour heterogeneity is needed to better translate the growing amount of information to patient stratified treatments. The first part of this thesis work concentrated on the functional in vitro and in vivo investigation of putative tumour suppressive characteristics of the EPH receptor A3 (EPHA3), a gene commonly mutated in human lung cancers. Our in vitro findings supported the tumour suppressive characteristics of EPHA3 and indicated that EPHA3-mediated tumour suppression was specifically dependent on its kinase activity. However, our in vivo investigation demonstrated that loss of EphA3 does not co-operate with two known genetic alterations of human lung cancer in murine lung tumourigenesis nor it effects lung morphogenesis. Hence, we conclude that our study demonstrates how functional validation of putative cancer genes can be challenged by biological complexity, which may result in acquired compensation or different functional roles in human and mice. The results from the second part of this thesis work showed that cells in the airways of mouse lungs had a higher propensity to develop faster growing and progressing lung tumours than the cells in the distal alveolar space when exposed to known lung cancer genetic alterations, namely expression of oncogenic Kras and loss of Lkb1 (KL). The lung tumours originated from the airways were predominantly classified as adenosquamous carcinomas (ASCs). ASCs showed elevated levels of genes associated with immunosuppression and a notable immune cell infiltration with an increase in the amount of possible myeloid-derived suppressor cells (MDSCs). The KL ASC model may thus represent a relevant preclinical model for the study of anti-MDSC immune therapy as a treatment for ASCs, which in humans represent a rare but aggressive type of lung cancer. Thus, the findings in this thesis work highlight the importance of the functional niche in the progression of lung cancer and, therefore, possibly affecting a response to treatment. Niche-specific investigation of lung cancer genetic alterations thus leads to a more accurate stratification of the preclinical in vivo models, simultaneously revealing relevant molecular mechanisms underlying lung cancer heterogeneity.
Originalspråkengelska
UtgivningsortHelsinki
Förlag
Tryckta ISBN978-951-51-1918-6
StatusPublicerad - 2016
MoE-publikationstypG5 Doktorsavhandling (artikel)

Vetenskapsgrenar

  • 3111 Biomedicinska vetenskaper

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title = "Studying the functional relevance of lung cancer genetic drivers in their physiological niche",
abstract = "Lung cancer is the leading cause of cancer related deaths worldwide. It is characterised with a high level of intra- and intertumour heterogeneity. Large lung cancer sequencing efforts have identified clear histopathology-specific genetic alteration patterns, which in the cases of lung adenocarcinomas are applied in clinics to direct treatment. Furthermore, lung cancer immunotherapy approaches have recently shown promising results in clinical trials. However, a deeper understanding of the functional importance of novel lung cancer genes as well as the lung cancer-related niche and cell type specific propensities leading to molecular and microenvironmental tumour heterogeneity is needed to better translate the growing amount of information to patient stratified treatments. The first part of this thesis work concentrated on the functional in vitro and in vivo investigation of putative tumour suppressive characteristics of the EPH receptor A3 (EPHA3), a gene commonly mutated in human lung cancers. Our in vitro findings supported the tumour suppressive characteristics of EPHA3 and indicated that EPHA3-mediated tumour suppression was specifically dependent on its kinase activity. However, our in vivo investigation demonstrated that loss of EphA3 does not co-operate with two known genetic alterations of human lung cancer in murine lung tumourigenesis nor it effects lung morphogenesis. Hence, we conclude that our study demonstrates how functional validation of putative cancer genes can be challenged by biological complexity, which may result in acquired compensation or different functional roles in human and mice. The results from the second part of this thesis work showed that cells in the airways of mouse lungs had a higher propensity to develop faster growing and progressing lung tumours than the cells in the distal alveolar space when exposed to known lung cancer genetic alterations, namely expression of oncogenic Kras and loss of Lkb1 (KL). The lung tumours originated from the airways were predominantly classified as adenosquamous carcinomas (ASCs). ASCs showed elevated levels of genes associated with immunosuppression and a notable immune cell infiltration with an increase in the amount of possible myeloid-derived suppressor cells (MDSCs). The KL ASC model may thus represent a relevant preclinical model for the study of anti-MDSC immune therapy as a treatment for ASCs, which in humans represent a rare but aggressive type of lung cancer. Thus, the findings in this thesis work highlight the importance of the functional niche in the progression of lung cancer and, therefore, possibly affecting a response to treatment. Niche-specific investigation of lung cancer genetic alterations thus leads to a more accurate stratification of the preclinical in vivo models, simultaneously revealing relevant molecular mechanisms underlying lung cancer heterogeneity.",
keywords = "Carcinogenesis, Cell Aging, +genetics, Cell Transformation, Neoplastic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Lung Neoplasms, +physiopathology, Mutation, Oligonucleotide Array Sequence Analysis, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Signal Transduction, Tumor Suppressor Protein p53, 3111 Biomedicine",
author = "Jenni Lahtela",
note = "M1 - 123 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:",
year = "2016",
language = "English",
isbn = "978-951-51-1918-6",
publisher = "University of Helsinki",
address = "Finland",

}

Studying the functional relevance of lung cancer genetic drivers in their physiological niche. / Lahtela, Jenni.

Helsinki : University of Helsinki, 2016. 123 s.

Forskningsoutput: AvhandlingDoktorsavhandlingSamling av artiklar

TY - THES

T1 - Studying the functional relevance of lung cancer genetic drivers in their physiological niche

AU - Lahtela, Jenni

N1 - M1 - 123 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:

PY - 2016

Y1 - 2016

N2 - Lung cancer is the leading cause of cancer related deaths worldwide. It is characterised with a high level of intra- and intertumour heterogeneity. Large lung cancer sequencing efforts have identified clear histopathology-specific genetic alteration patterns, which in the cases of lung adenocarcinomas are applied in clinics to direct treatment. Furthermore, lung cancer immunotherapy approaches have recently shown promising results in clinical trials. However, a deeper understanding of the functional importance of novel lung cancer genes as well as the lung cancer-related niche and cell type specific propensities leading to molecular and microenvironmental tumour heterogeneity is needed to better translate the growing amount of information to patient stratified treatments. The first part of this thesis work concentrated on the functional in vitro and in vivo investigation of putative tumour suppressive characteristics of the EPH receptor A3 (EPHA3), a gene commonly mutated in human lung cancers. Our in vitro findings supported the tumour suppressive characteristics of EPHA3 and indicated that EPHA3-mediated tumour suppression was specifically dependent on its kinase activity. However, our in vivo investigation demonstrated that loss of EphA3 does not co-operate with two known genetic alterations of human lung cancer in murine lung tumourigenesis nor it effects lung morphogenesis. Hence, we conclude that our study demonstrates how functional validation of putative cancer genes can be challenged by biological complexity, which may result in acquired compensation or different functional roles in human and mice. The results from the second part of this thesis work showed that cells in the airways of mouse lungs had a higher propensity to develop faster growing and progressing lung tumours than the cells in the distal alveolar space when exposed to known lung cancer genetic alterations, namely expression of oncogenic Kras and loss of Lkb1 (KL). The lung tumours originated from the airways were predominantly classified as adenosquamous carcinomas (ASCs). ASCs showed elevated levels of genes associated with immunosuppression and a notable immune cell infiltration with an increase in the amount of possible myeloid-derived suppressor cells (MDSCs). The KL ASC model may thus represent a relevant preclinical model for the study of anti-MDSC immune therapy as a treatment for ASCs, which in humans represent a rare but aggressive type of lung cancer. Thus, the findings in this thesis work highlight the importance of the functional niche in the progression of lung cancer and, therefore, possibly affecting a response to treatment. Niche-specific investigation of lung cancer genetic alterations thus leads to a more accurate stratification of the preclinical in vivo models, simultaneously revealing relevant molecular mechanisms underlying lung cancer heterogeneity.

AB - Lung cancer is the leading cause of cancer related deaths worldwide. It is characterised with a high level of intra- and intertumour heterogeneity. Large lung cancer sequencing efforts have identified clear histopathology-specific genetic alteration patterns, which in the cases of lung adenocarcinomas are applied in clinics to direct treatment. Furthermore, lung cancer immunotherapy approaches have recently shown promising results in clinical trials. However, a deeper understanding of the functional importance of novel lung cancer genes as well as the lung cancer-related niche and cell type specific propensities leading to molecular and microenvironmental tumour heterogeneity is needed to better translate the growing amount of information to patient stratified treatments. The first part of this thesis work concentrated on the functional in vitro and in vivo investigation of putative tumour suppressive characteristics of the EPH receptor A3 (EPHA3), a gene commonly mutated in human lung cancers. Our in vitro findings supported the tumour suppressive characteristics of EPHA3 and indicated that EPHA3-mediated tumour suppression was specifically dependent on its kinase activity. However, our in vivo investigation demonstrated that loss of EphA3 does not co-operate with two known genetic alterations of human lung cancer in murine lung tumourigenesis nor it effects lung morphogenesis. Hence, we conclude that our study demonstrates how functional validation of putative cancer genes can be challenged by biological complexity, which may result in acquired compensation or different functional roles in human and mice. The results from the second part of this thesis work showed that cells in the airways of mouse lungs had a higher propensity to develop faster growing and progressing lung tumours than the cells in the distal alveolar space when exposed to known lung cancer genetic alterations, namely expression of oncogenic Kras and loss of Lkb1 (KL). The lung tumours originated from the airways were predominantly classified as adenosquamous carcinomas (ASCs). ASCs showed elevated levels of genes associated with immunosuppression and a notable immune cell infiltration with an increase in the amount of possible myeloid-derived suppressor cells (MDSCs). The KL ASC model may thus represent a relevant preclinical model for the study of anti-MDSC immune therapy as a treatment for ASCs, which in humans represent a rare but aggressive type of lung cancer. Thus, the findings in this thesis work highlight the importance of the functional niche in the progression of lung cancer and, therefore, possibly affecting a response to treatment. Niche-specific investigation of lung cancer genetic alterations thus leads to a more accurate stratification of the preclinical in vivo models, simultaneously revealing relevant molecular mechanisms underlying lung cancer heterogeneity.

KW - Carcinogenesis

KW - Cell Aging

KW - +genetics

KW - Cell Transformation, Neoplastic

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Lung Neoplasms

KW - +physiopathology

KW - Mutation

KW - Oligonucleotide Array Sequence Analysis

KW - Protein-Serine-Threonine Kinases

KW - Proto-Oncogene Proteins

KW - Receptor Protein-Tyrosine Kinases

KW - Signal Transduction

KW - Tumor Suppressor Protein p53

KW - 3111 Biomedicine

M3 - Doctoral Thesis

SN - 978-951-51-1918-6

PB - University of Helsinki

CY - Helsinki

ER -