Dokument

Zusammenfassung:
Die onkogene aktivierende Mutation von Kras stellt ein Schlüsselereignis in der Entstehung eines Pankreaskarzinoms (PDAC) dar und findet sich bereits in metaplastischen exokrinen Arealen des Organs. Allerdings ist die isolierte onkogene Aktivierung von Kras nicht suffizient, um die Pankreaskarzinogenese über die Stadien der Präinvasivität hinaus zu akzelerieren, sondern setzt die funktionelle Kooperation mit inflammatorischen Signalwegen voraus, die z.B. im Kontext einer chronischen Pankreatitis induziert werden. Zu den zentralen inflammationsresponsiven Ereignissen in der Karzinogenese des Pankreas zählt die Aktivierung EGFR-abhängiger Signalwege. Trotz zahlreicher Arbeiten, die die Relevanz der EGFR-Signaltransduktion in der Entstehung und Progression des Pankreaskarzinoms untersuchten, blieb der Mechanismus der EGFR-abhängigen azinär-duktalen Transdifferenzierung bisher ungeklärt. In Vorarbeiten charakterisierte die Arbeitsgruppe von Prof. Ellenrieder den inflammatorischen Transkriptionsfaktor Nuclear Activated Factor of T-cells c1 (NFATc1) als essentielles onkogenes Protein in der Genese und Progression des Pankreaskarzinoms. In der vorliegenden Arbeit sollte die Funktion von NFATc1 innerhalb der inflammationsgetriggerten, EGFR-abhängigen Pankreaskarzinomentstehung untersucht werden. Die Ergebnisse dieser Arbeit zeigen eine robuste EGFR-abhängige Induktion der NFATc1-Expression in metaplastischen Pankreasarealen. Mechanistisch begünstigt die Aktivierung des EGFR-Signalwegs die Bildung eines NFATc1;c-Jun-Partnerkomplexes, der durch direkte Promotorbindung die transkriptionelle Aktivierung des epithelialen Transkriptionsfaktors Sox9 kontrolliert und somit azinär-duktale Transdifferenzierungsvorgänge initiiert. Die pharmakologische und genetische NFATc1-Inhibition hingegen führt sowohl in vitro als auch in vivo zu einer Reduktion der EGFR-vermittelten azinär-duktalen Transdifferenzierung und Pankreasmetaplasie. Diese Arbeit beschreibt NFATc1 als zentralen Mediator duktaler Transdifferenzierungsprozesse in der EGFR-vermittelten Pankreaskarzinomentstehung und charakterisiert den Transkriptionsfaktor als vielversprechendes Zielprotein für pharmakologische Ansätze der Pankreaskarzinomprophylaxe bei Patienten mit chronischer Pankreatitis.

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