Understanding TGFβ driven mitotic errors and chromosomal instability in SMAD4-deficient PDAC subtypes

点击翻译按钮获取中文摘要

Whole chromosome instability (W-CIN) is a hallmark of cancer and is defined as an increased rate of chromosome missegregation during mitosis leading to evolving aneuploidy. By perpetually altering the genetic composition of cancer cells W-CIN can fuel clonal evolution of tumors, tumor progression and the development of therapy resistance. Despite the importance of CIN in cancer the molecular mechanisms causing CIN are still incompletely understood. In PDAC, the role CIN is overall poorly defined. Moreover, the type of mitotic errors and aneuploidy as well as the molecular mechanisms leading to W-CIN have not been addressed in PDAC so far. Our preliminary results surprisingly indicated that TGFβ signaling is required for the induction of W-CIN in various cancer cells and also in PDAC cells. Mechanistically, we found that basal TGFβ signaling mediates increased microtubule dynamics within mitotic spindles, which causes abnormal microtubule-kinetochore attachments leading to whole chromosome missegregation. Moreover, we found that loss of SMAD4, which represents one of the major genetic aberrations in PDAC, fosters the induction of W-CIN, possibly by re-directing TGFβ signaling into non-SMAD signaling pathways. Based on these results we hypothesize that PDAC subgroups characterized by high TGFβ signaling, but also by loss of SMAD4 are prone for the induction of chromosomal stability, which supports tumor progression, tumor aggressiveness and therapy resistance. The scientific project 6 will systematically investigate the presence and the mechanisms of W-CIN in PDAC, which will lead to a first definition of PDAC sub-types characterized by mitotic errors and W-CIN. Furthermore, the planned experiments aim to elucidate the nature of mitotic errors present in chromosomally unstable PDACs, both in cell lines and in PDX-derived cells. We will investigate the CIN-mediating role of TGFβ signaling and in particular of non-SMAD pathways in PDAC subgroups with loss of SMAD4. By interfering with TGFβ signaling and with microtubule dynamics we will develop experimental routes to suppress CIN in PDAC cell models to directly address the question for the role of CIN in acquiring aggressive tumor phenotypes and in mediating resistance towards clinically relevant therapy regimens.