| 1. |
- Anderberg, C., et al.
(författare)
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Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination
- 2013
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 210:3, s. 563-579
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Tidskriftsartikel (refereegranskat)abstract
- Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.
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| 2. |
- Cortez, Eliane
(författare)
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Exploring the functional heterogeneity of the tumor microenvironment
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tumors are complex entities, composed of different functional populations of malignant and stromal cells. There is an emerging importance to understand previously unmapped communication routes between different cell and non-cell compartments of the tumor microenvironment. Targeted drugs have been used for years in an attempt to block essential pathways for tumor growth. Specifically, drugs targeting tumor angiogenesis have shown significant success in different types of tumors. However, as effective as some of these compounds are, durable responses are rare and resistance does ultimately occur. Studies exploring therapeutic resistance have largely focused on endothelial cells (ECs). However, more recent reports suggest that development of resistance can be conferred by functional alterations of supporting cells like pericytes. Pericytes are a heterogeneous and highly mystifyingpopulation of mural cells and have been for years suggested to protect ECs from anti-angiogenic insults, promote vessel regrowth and tumor progression. However, most of the knowledge on pericytes in tumor growth is confounding and often conflicting.In the first part of this thesis, we investigated several aspects of pericyte function during tumor progression. Using an experimental model of pancreatic neuroendocrine tumors (PanNETs), we characterized the nature of signals exchanged between pericytes and ECs in tumor vessels. We showed that pericytes, when in the vicinity of ECs, promote the upregulation of genes involved in cell survival like Bcl-w. We further demonstrated that upregulation of survival genes is dependent on autocrine vascular endothelial growth factor A (VEGF-A) signaling in ECs. Moreover, we showed that the amount of pericytes expressing alpha-smooth muscle actin (α-SMA) is increased in the tumor parenchyma upon anti-VEGF-A therapy. This highlights the potential value of using pericyte marker expression to predict clinical response to anti-vascular therapy. Finally, we characterized a novel imaging tool, the PDGFRβ-Affibody, a small molecule showing specific binding to platelet derived growth factor receptor beta (PDGFRβ) in tumors. This Affibody molecule holds the potential of being used to identify pericytes in tumors and to deliver cytotoxic compounds directly to the tumor microvasculature. In the second part of this thesis, we investigated the biological function of the latest identified ligand for PDGFRβ, PDGF-DD, in tumor progression. Making use of a newly generated Pdgfd knockout mouse, we demonstrated that growth of PanNET in the RIP1-TAg2 model is significantly impaired in the absence of PDGF-DD. Deficient PDGF-DD signaling did not affect angiogenesis or pericyte recruitment to blood vessels. Instead, we found that PDGF-DD stimulated the proliferation of the bulk tumor cell population by inducing expression of mitogenic factors by a rare population of malignant cells expressing PDGFRβ.The existence of a heterogeneous population of tumor cells, marked by rare expression of PDGFRβ in malignant clones, was further confirmed in a cohort of human primary and metastatic PanNET.Our studies emphasize the prevalent theory that targeting multiple compartments of the tumor microenvironment may represent a viable alternative to prevent resistance and achieve durable responses in patients. However, elucidating the relationship between the heterogeneous composition of tumors and the therapeutic outcome is still a significant challenge.
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| 3. |
- Cortez, Eliane, et al.
(författare)
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Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD.
- 2016
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 113:7, s. 864-873
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Tidskriftsartikel (refereegranskat)abstract
- Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.
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| 4. |
- Cortez, Eliane, et al.
(författare)
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Functional subsets of mesenchymal cell types in the tumor microenvironment.
- 2014
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 25:Jan 7, s. 3-9
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Forskningsöversikt (refereegranskat)abstract
- In the field of tumor biology, increasing attention is now focused on the complex interactions between various constituent cell types within the tumor microenvironment as being functionally important for the etiology of the disease. The detailed description of tumor-promoting properties of cancer-associated fibroblasts, endothelial cells, pericytes, and immune cells, introduces novel potential drug targets for improved cancer treatments, as well as a rationale for exploring the tumor stroma as a previously unchartered source for prognostic or predictive biomarkers. However, recent work highlights the fact that cellular identity is perhaps too broadly defined and that subdivision of each cell type may reveal functionally distinct subsets of cells. Here, we will review our current understanding of the diversity of different subsets of mesenchymal cells, i.e., cancer-associated fibroblasts and pericytes, residing within the tumor parenchyma.
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| 5. |
- Eleftheriou, Nikolas M., et al.
(författare)
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Compound genetically engineered mouse models of cancer reveal dual targeting of ALK1 and endoglin as a synergistic opportunity to impinge on angiogenic TGF-β signaling
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:51, s. 84314-84325
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis occurs early in tumor development, sustains primary tumor growth and provides a route for metastatic escape. The TGF-β family receptors modulate angiogenesis via endothelial-cell specific pathways. Here we investigate the interaction of two such receptors, ALK1 and endoglin, in pancreatic neuroendocrine tumors (PanNET). Independently, ALK1 and endoglin deficiencies exhibited genetically divergent phenotypes, while both highly correlate to an endothelial metagene in human and mouse PanNETs. A concurrent deficiency of both receptors synergistically decreased tumor burden to a greater extent than either individual knockdown. Furthermore, the knockout of Gdf2 (BMP9), the primary ligand for ALK1 and endoglin, exhibited a mixed phenotype from each of ALK1 and endoglin deficiencies; overall primary tumor burden decreased, but hepatic metastases increased. Tumors lacking BMP9 display a hyperbranching vasculature, and an increase in vascular mesenchymal-marker expression, which may be implicit in the increase in metastases. Taken together, our work cautions against singular blockade of BMP9 and instead demonstrates the utility of dual blockade of ALK1 and endoglin as a strategy for antiangiogenic therapy in PanNET.
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| 6. |
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| 7. |
- Roswall, Pernilla, et al.
(författare)
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Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling
- 2018
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 24, s. 463-473
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Tidskriftsartikel (refereegranskat)abstract
- Breast tumors of the basal-like, hormone receptor-negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support most, if not all, hallmarks of cancer progression. Here we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention of PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor-positive state that enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that specification of breast cancer to the basal-like subtype is under microenvironmental control and is therapeutically actionable.
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