Heidelberg Institute for Stem Cell Technology and Experimental Medicine

Heidelberg, Germany

Heidelberg Institute for Stem Cell Technology and Experimental Medicine

Heidelberg, Germany
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Insua-Rodriguez J.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Insua-Rodriguez J.,German Cancer Research Center | Oskarsson T.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Oskarsson T.,German Cancer Research Center
Advanced Drug Delivery Reviews | Year: 2016

The extracellular matrix (ECM) is increasingly recognized as an important regulator in breast cancer. ECM in breast cancer development features numerous changes in composition and organization when compared to the mammary gland under homeostasis. Matrix proteins that are induced in breast cancer include fibrillar collagens, fibronectin, specific laminins and proteoglycans as well as matricellular proteins. Growing evidence suggests that many of these induced ECM proteins play a major functional role in breast cancer progression and metastasis. A number of the induced ECM proteins have moreover been shown to be essential components of metastatic niches, promoting stem/progenitor signaling pathways and metastatic growth. ECM remodeling enzymes are also markedly increased, leading to major changes in the matrix structure and biomechanical properties. Importantly, several ECM components and ECM remodeling enzymes are specifically induced in breast cancer or during tissue regeneration while healthy tissues under homeostasis express exceedingly low levels. This may indicate that ECM and ECM-associated functions may represent promising drug targets against breast cancer, providing important specificity that could be utilized when developing therapies. © 2015 Elsevier B.V.


Ehninger A.,German Cancer Research Center | Trumpp A.,German Cancer Research Center | Trumpp A.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Journal of Experimental Medicine | Year: 2011

Stem cell niches are defined as the cellular and molecular microenvironments that regulate stem cell function together with stem cell autonomous mechanisms. This includes control of the balance between quiescence, self-renewal, and differentiation, as well as the engagement of specific programs in response to stress. In mammals, the best understood niche is that harboring bone marrow hematopoietic stem cells (HSCs). Recent studies have expanded the number of cell types contributing to the HSC niche. Perivascular mesenchymal stem cells and macrophages now join the previously identified sinusoidal endothelial cells, sympathetic nerve fibers, and cells of the osteoblastic lineage to form similar, but distinct, niches that harbor dormant and self-renewing HSCs during homeostasis and mediate stem cell mobilization in response to granulocyte colony-stimulating factor. © 2011 Ehninger and Trumpp.


Oskarsson T.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Oskarsson T.,German Cancer Research Center
Breast | Year: 2013

The extracellular matrix (ECM) is composed of highly variable and dynamic components that regulate cell behavior. The protein composition and physical properties of the ECM govern cell fate through biochemical and biomechanical mechanisms. This requires a carefully orchestrated and thorough regulation considering that a disturbed ECM can have serious consequences and lead to pathological conditions like cancer. In breast cancer, many ECM proteins are significantly deregulated and specific matrix components promote tumor progression and metastatic spread. Intriguingly, several ECM proteins that are associated with breast cancer development, overlap substantially with a group of ECM proteins induced during the state of tissue remodeling such as mammary gland involution. Fibrillar collagens, fibronectin, hyaluronan and matricellular proteins are matrix components that are common to both involution and cancer. Moreover, some of these proteins have in recent years been identified as important constituents of metastatic niches in breast cancer. In addition, specific ECM molecules, their receptors or enzymatic modifiers are significantly involved in resistance to therapeutic intervention. Further analysis of these ECM proteins and the downstream ECM mediated signaling pathways may provide a range of possibilities to identify druggable targets against advanced breast cancer. © 2013 Elsevier Ltd.


Descot A.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Descot A.,German Cancer Research Center | Oskarsson T.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Oskarsson T.,German Cancer Research Center
Experimental Cell Research | Year: 2013

In cancer, the microenvironment plays an important role of supporting the outgrowth of new tumors in distant organs i.e. the formation of metastasis. The interplay between cancer cells and the host stroma leads to generation of an active microenvironment termed a metastatic niche that effectively supports cancer progression and outgrowth of metastasis. The generation and development of the niche is intricately linked to cancer progression. Metastatic niches are highly dynamic interactions that can be forged by diverse mechanisms and continue to develop as the cancer progresses. The composition of the niche is increasingly being characterized and new niche components are being identified. The extracellular matrix (ECM), secreted enzymes, growth factors, cytokines and other molecules that carry information to cancer cells are essential parts of the metastatic niche. The sources of this molecular milieu are multiple cell types - local or recruited to the site of metastasis - and in some cases the cancer cells themselves. To understand metastatic progression it is essential to dissect the niche composition and identify the sources of niche components. With future analyses of the metastatic niche, significant opportunities can arise to identify novel targets for cancer therapy. Targeting the metastatic niche may be essential to treat and inhibit the progression of metastasis. © 2013 Elsevier B.V.


Acharyya S.,Sloan Kettering Cancer Center | Oskarsson T.,Sloan Kettering Cancer Center | Oskarsson T.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Vanharanta S.,Sloan Kettering Cancer Center | And 11 more authors.
Cell | Year: 2012

Metastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b+Gr1+ myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells. TNF-α via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention. © 2012 Elsevier Inc.


Oskarsson T.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Massague J.,Sloan Kettering Cancer Center
EMBO Journal | Year: 2012

Metastatic niches support the survival and fitness of disseminated tumour cells (DTCs) in otherwise inhospitable tissue environments. The components of metastatic niches have remained a matter of conjecture, but recent reports, including one in a current issue of Nature, point at the extracellular matrix (ECM) proteins periostin and tenascin C (TNC) as key metastatic niche molecules. By enhancing Wnt and Notch signalling in cancer cells, these proteins provide physical as well as signalling support for metastasis-initiating cells. These findings underscore the importance of the ECM environment in cancer and provide potential drug targets against metastasis. © 2012 European Molecular Biology Organization | All Rights Reserved.


Essers M.A.G.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Trumpp A.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Molecular Oncology | Year: 2010

Transient or long-term quiescence, the latter referred to as dormancy are fundamental features of at least some adult stem cells. The status of dormancy is likely a critical mechanism for the observed resistance of normal HSCs and leukemic stem cells (LSCs) to anti-proliferative chemotherapy. Recent studies have revealed cytokines such as Interferon-alpha (IFNα) and G-CSF as well as arsenic trioxide (As2O3) to be efficient agents for promoting cycling of dormant HSCs and LSCs. Most interestingly, such cell cycle activated stem cells become exquisitely sensitive to killing by different chemotherapeutic agents, suggesting that dormant LSCs in patients may be targeted by a sequential two-step protocol involving an initial activation by IFNα, G-CSF or As2O3, followed by targeted chemotherapy. © 2010 Federation of European Biochemical Societies.


Patent
Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Date: 2012-03-08

This invention relates to a novel method for analyzing circulating tumor cells of a patient for the presence of metastasis-initiating cells. The method comprises the step of detecting cells exhibiting the simultaneous presence of c-MET, CD44 and CD47. The invention further relates to novel kits, novel methods for treating patients, and novel bifunctional analytes.


Jiang W.,University of Lausanne | Ferrero I.,University of Lausanne | Laurenti E.,University of Lausanne | Trumpp A.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | MacDonald H.R.,University of Lausanne
Blood | Year: 2010

The murine gut epithelium contains a large population of thymus-derived intraepithelial lymphocytes (IELs), including both conventional CD4+ and CD8αβ+ T cells (expressing T-cell receptor αβ [TCRαβ]) and unconventional CD8αα + T cells (expressing either TCRαβ or TCRγδ). Whereas conventional IELs are widely accepted to arise from recirculation of activated CD4+ and CD8αβ+ T cells from the secondary lymphoid organs to the gut, the origin and developmental pathway of unconventional CD8αα IELs remain controversial. We show here that CD4-Cre-mediated inactivation of c-Myc, a broadly expressed transcription factor with a wide range of biologic activities, selectively impairs the development of CD8αα TCRαβ IELs. In the absence of c-Myc, CD4 - CD8- TCRαβ+ thymic precursors of CD8αα TCRαβ IELs are present but fail to develop on adoptive transfer in immunoincompetent hosts. Residual c-Myc-deficient CD8αα TCRαβ IEL display reduced proliferation and increased apoptosis, which correlate with significantly decreased expression of interleukin-15 receptor subunits and lower levels of the antiapoptotic protein Bcl-2. Transgenic overexpression of human BCL-2 resulted in a pronounced rescue of CD8αα TCRαβ IEL in c-Myc-deficient mice. Taken together, our data support a model in which c-Myc controls the development of CD8αα TCRαβ IELs from thymic precursors by regulating interleukin-15 receptor expression and consequently Bcl-2-dependent survival. © 2010 by The American Society of Hematology.


Prendergast A.M.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Essers M.A.G.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Annals of the New York Academy of Sciences | Year: 2014

The immune response to infection is a rapid and multifaceted process. Infection affects homeostasis within the hematopoietic stem cell (HSC) niche, as lost immune cells must be replaced by HSCs. During the immune response, interferon is produced. Surprisingly, HSCs respond directly to interferon, entering the cell cycle from even the most dormant state. The complex response of both the HSCs and the niche to infection is a unique platform on which to consider HSC-niche interactions. Here, we comment on the contribution of the immune system to the niche and on the direct and indirect effect that infection has on HSCs in the niche. © 2014 New York Academy of Sciences.

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