Abstract SY28-02: Interactions between cancer stem cells and their niche govern metastatic colonization
Authors: Ilaria Malanchi, Albert Santamaria-Martínez, Evelyn Susanto, Hong Peng, Hans-Anton Lehr, Jean-Francois Delaloye, Joerg Huelsken
Journal: Cancer Research (2012)

Abstract Metastatic growth in distant organs is the major cause of cancer mortality. Formation of metastasis is a multi-step process with several rate-limiting steps. While dissemination of tumour cells appears to be an early and frequent event, successful initiation of metastatic growth, a process termed “metastatic colonization,” is rather inefficient for many cancer types and accomplished only by a minority of cancer cells that reach distant sites. Prevalent target sites are characteristic for many tumour entities. The inefficiency of the metastatic process suggests two possibilities: a differential potential of the disseminated cancer cells to grow at the secondary sites or an inadequate support by distant tissues. We aimed at exploring limiting factors that determine metastatic success using the MMTVPyMT mouse breast cancer model which spontaneously metastasizes to the lungs. Considering that the disseminated cancer cells might have a differential metastatic potential, we investigated whether the recently identified cancer stem cells (CSCs, also termed tumour initiating cells), might be also relevant for the metastatic process. We found that a small population of cancer stem cells (CSCs) is critical for metastatic colonization. These CSCs represent a stable population of tumour cells which selectively survive and proliferate upon metastatic seeding and thereby drive the initial expansion of cancer cells at the secondary site. In contrast, nonCSCs fail to grow, are rapidly lost and do not de-differentiate into CSCs. Yet, the numbers of CSCs appear to be too high to fully explain the inefficiency of metastatic nodule formation, indicating that additional factors restrict successful metastatic colonization. Stem cells are suspected to rely on signals from their stromal environment such as localized growth factors that can affect stem cell maintenance and proliferation. In this study, we find stromal niche signals to be crucial for this process. We identify the extracellular matrix (ECM) component POSTN to be expressed by fibroblasts in the normal tissue exclusively in response to tumour cell infiltration. Infiltrating tumour cells induce stromal POSTN expression in the secondary target organ via TGFb3 secretion. Importantly the induction of POSTN at the target site is essential for the metastatic process. Indeed, generation of a POSTN null mouse revealed that the metastatic process is heavily compromised in the absence of POSTN. Similarly, cancer cells unable to induce POSTN expression at the target site due to blocking of TGFb3 signaling show poor metastatic activity. We further show that this ECM protein is required to allow maintenance of cancer stem cells: the cells driving the metastatic process. To understand how POSTN connects to the mechanisms that control stem cell maintenance we characterize its binding partners. We found that POSTN is able to bind Wnt ligands and therefore increase Wnt signaling. In vivo we observed Wnt signaling activity selectively in the CSCs population and this activity is abrogated in absence of POSTN. Finally, the metastatic activity of tumour cells with constitutively active Wnt signaling is independent of POSTN presence. Thus, POSTN acts as a niche component that can promote stem cell maintenance and metastatic colonization by augmenting Wnt signaling. We suggest that the education of stromal cells by infiltrating tumour cells is an important step in metastatic colonization and that preventing de-novo niche formation may represent a novel treatment strategy against metastatic disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY28-02. doi:1538-7445.AM2012-SY28-02