Elucidation of intratumoral heterogeneity in Kras-driven cancers

Projektinformationen

INTUMORX

ID Finanzhilfevereinbarung: 716162

DOI 10.3030/716162

Das Projekt endete am 20 Oktober 2017

EK-Unterschriftsdatum 2 Mai 2017

Startdatum 1 Juli 2017

Enddatum 30 Juni 2022

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten € 1 972 905,00

EU-Beitrag € 1 972 905,00

Koordiniert durch

HELSINGIN YLIOPISTO
Finland

Ziel

The considerable variability within tissue microenvironments as well as the multiclonality of cancers leads to intratumoral heterogeneity. This increases the probablility of cellular states that promote resistance to therapy and eventually lead to reconstitution of the tumor by treatment-resistant cancer cells, which in some cases have properties of normal tissue stem cells. Wnt signals are important in the maintenance of stem cells in various epithelial tissues, including in lung development and regeneration. We hypothesized that Wnt signals contribute to tumor heterogeneity in genetically engineered KrasG12D; Tp53Δ/Δ (”KP”) mouse lung adenocarcinomas (LUAD). We observed that a subpopulation of LUAD cells exhibited high Wnt reporter activity and had increased tumor forming ability, which could be suppressed by silencing of Wnt signaling pathway components or by small molecule Wnt inhibitors in vitro and in vivo. KP LUAD cells show hierarchical features with two distinct populations, one with increased Wnt reporter activity and another forming a niche that provides the Wnt signal. Lineage-tracing experiments in the autochthonous KP tumors demonstrated that Wnt responder cells have increased tumor propagation ability in vivo. Strikingly, selective ablation of the Wnt responder cells resulted in tumor stasis. CRISPR-based targeting or small molecules targeting Wnt signaling reduced tumor growth and prolonged survival in the autochthonous KP mouse lung cancer model. These results indicate that maintenance of heterogeneity within tumors may be advantageous for the tumor cell population collectively. We propose to elucidate the molecular and cellullar mechanisms that control stem-like and niche cell phenotypes using a combination of novel lentiviral vectors and genetically modified mice in the context of the KP LUAD model. These efforts may lead to novel therapeutic concepts in human lung cancer.

Wissenschaftliches Gebiet

• medical and health sciences › clinical medicine › oncology › prostate cancer
• medical and health sciences › clinical medicine › oncology › lung cancer
• medical and health sciences › medical biotechnology › cells technologies › stem cells

Schlüsselbegriffe

• Wnt
• Lgr5
• Kras
• lung cancer
• cancer stem cell
• cancer heterogeneity

Programm/Programme

• H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme

Thema/Themen

• ERC-2016-STG - ERC Starting Grant

Aufforderung zur Vorschlagseinreichung

ERC-2016-STG

Finanzierungsplan

ERC-STG - Starting Grant

Gastgebende Einrichtung

HELSINGIN YLIOPISTO

• Netto-EU-Beitrag: € 1 972 905,00
• Adresse: YLIOPISTONKATU 3 ; 00014 Helsingin Yliopisto ; Finnland
• Region: Manner-Suomi › Helsinki-Uusimaa › Helsinki-Uusimaa
• Aktivitätstyp: Higher or Secondary Education Establishments
• Gesamtkosten: € 1 972 905,00

Begünstigte (1)

HELSINGIN YLIOPISTO

Finnland

• Netto-EU-Beitrag: € 1 972 905,00
• Adresse: YLIOPISTONKATU 3 ; 00014 Helsingin Yliopisto
• Region: Manner-Suomi › Helsinki-Uusimaa › Helsinki-Uusimaa
• Aktivitätstyp: Higher or Secondary Education Establishments
• Gesamtkosten: € 1 972 905,00