Directly to content
  1. Publishing |
  2. Search |
  3. Browse |
  4. Recent items rss |
  5. Open Access |
  6. Jur. Issues |
  7. DeutschClear Cookie - decide language by browser settings

Stromal loss of JUNB promotes distant metastasis

Wutschka, Juliane

[img] PDF, English
Download (6MB) | Terms of use

Citation of documents: Please do not cite the URL that is displayed in your browser location input, instead use the DOI, URN or the persistent URL below, as we can guarantee their long-time accessibility.

Abstract

The AP-1 family member JUNB is a context dependent transcriptional regulator implicated in essential cellular processes, such as proliferation, differentiation and inflammation. JUNB has furthermore been described to function both as tumor suppressor and as oncogene, largely dependent on the tumor entity. JUNB loss of function is predominantly observed in leukemia, for example in chronic myeloid leukemia as well as acute myeloid leukemia. In contrast, JUNB is frequently overexpressed in solid tumors, such as breast and colon cancer, but also in a multitude of lymphomas. Functionally, JUNB has been associated with invasion and metastasis. Yet, the majority of data linking JUNB to disease progression have been obtained either in in vitro experiments or are based on correlational studies. All studies assessing the contribution of JUNB to metastasis have focused on JUNB expression in the tumor cells themselves. JUNB is, however, an essential regulator in a vast plethora of cells of the tumor microenvironment. Such being the case, JUNB is crucial for the development and homeostasis of the blood vascular system and has also been implicated in the formation of the lymphatic system. Moreover, JUNB controls the differentiation of T helper cells and is required for the activation of macrophages. Thus, the aim of this dissertation was to elucidate the functional consequences of JUNB loss in the stroma on metastasis in vivo in mice. For this purpose, elaborate spontaneous metastasis assays involving primary tumor resections were performed using conditional Junb knockout mice and syngeneic cell lines. In line with previous findings of the group, primary tumor growth was unaffected by stromal deletion of Junb. Strikingly though, stromal JUNB loss facilitated distant metastasis to the lungs in a breast cancer model developing spontaneous metastasis. Yet, tumor cell extravasation and metastatic colonization were not influenced by Junb ablation, implying that JUNB controls the initial steps of the metastatic cascade. In order to mechanistically decipher the contribution of stromal JUNB to metastasis, various cellular compartments were analyzed for JUNB-dependent changes. Despite its essential role in vascular biology, no defects in the blood and lymphatic vascular system could be determined in Junb knockout mice. Similarly, fibroblast density was unaltered upon ablation of stromal Junb. Remarkably, a prominent accumulation of immune cells, in particular of neutrophils, was found upon JUNB loss in primary breast tumors and even more strikingly in pre-metastatic lungs. Concomitantly, neutrophil recruiting factors, such as Tnfα and Il-1β, were upregulated upon JUNB loss. Bone marrow transplantation experiments further pointed towards neutrophil recruitment being mediated by deletion of Junb in the stroma rather than a neutrophil-intrinsic mechanism. In an attempt to directly link neutrophil accumulation to enhanced metastasis, neutrophils were ablated pharmacologically using an anti-LY6G antibody. Yet, depletion efficiency was too low to establish direct functional proof. The experiment did, however, clearly confirm the initial data that JUNB loss in the stroma promotes breast cancer metastasis. In conclusion, the data of this dissertation provide the first functional evidence that deletion of stromal Junb indeed facilitates metastatic spread possibly by the formation of a pre-metastatic niche. Since JUNB is a target of Mitogen-activated protein kinase (MAPK) signaling, these findings are especially important with regard to the development of novel targeted approaches for cancer therapy. Unless cancer cells can be targeted specifically, strategies resulting in JUNB loss in the microenvironment should be avoided.

Item Type: Dissertation
Supervisor: Angel, Prof. Dr. Peter
Date of thesis defense: 22 May 2019
Date Deposited: 28 May 2019 08:53
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
About | FAQ | Contact | Imprint |
OA-LogoDINI certificate 2013Logo der Open-Archives-Initiative