Angiogenesis and Tumor Microenvironment
Our laboratory investigates the interactions between genetically altered cancer cells and the ostensibly normal host tissues in which tumors arise, progress and develop to metastatic disease. We focus on the cross talk between malignant cells and the vascular system, immune cells, and secreted extracellular vesicles (exosomes), and the mechanisms whereby these heterotypic interactions regulate tumor progression in experimental cancer models. This is being studied primarily in transgenic mouse models of breast and lung cancer, in which both malignant and host cells are genetically engineered to be visualized or depleted, or to modify their expression of genes of interest. Furthermore, we examine how the interplay between the tumor and the host can be harnessed for improving tumor response to anti-cancer therapies.
04/2019. Congratulations to Chiara, Tim and Florent on the acceptance of their paper in Cell Reports!
11/2018. Congratulations to Ioanna and Chiara on the acceptance of their paper in Nature Cell Biology!
08/2018. Welcome back, Caleb!
08/2018. Our review article on perivascular macrophages has been published in Nature Reviews Immunology.
05/2018. The review article “Consensus guidelines for the use and interpretation of angiogenesis assays” is now published in Angiogenesis Journal.
05/2018. Our work has been featured in Gen Suisse
02/2018. Congratulations to Ioanna and Martina on the acceptance of their papers in Cell Reports and Science Translational Medicine!
11/2017. Miki is the 2017 recipient of the Robert Wenner Prize for cancer research, awarded by the Swiss Cancer League.
11/2017. Congratulations to Mario on the acceptance of his paper in Nature Methods!
12/2016. Miki has been awarded an ERC consolidator grant (CoG). The project will develop a new generation of cancer vaccines based on engineered dendritic cells.
SELECTED RECENT PUBLICATIONS
Cianciaruso, C.*, Beltraminelli, T.*, Duval, F.*, Nassiri, S., Hamelin, R., Mozes, A., Gallart-Ayala, H., Ceada Torres, G., Torchia, B., Ries, C.H., Ivanisevic, J., & De Palma, M. Molecular profiling and functional analysis of macrophage-derived tumor extracellular vesicles. Cell Rep. 2019 June 4;27(10):3062-3080.e11.
Key findings: We develop methods for the analysis of extracellular vesicles secreted by tumor-associated macrophages (TAM-EVs). Proteomic and lipidomic profiling indicates that TAM-EVs carry modulators of inflammation and lipid metabolism that could influence the properties of the tumor immune microenvironment.
Keklikoglou, I.*, Cianciaruso, C.*, Güç, E., Squadrito, M.L., Spring, L.M., Tazzyman, S., Lambein, L., Poissonnier, A., Ferraro, G.B., Baer, C., Cassará, A., Guichard, A., Iruela-Arispe, M.L., Lewis, C.E., Coussens, L.M., Bardia, A., Jain, R.K., Pollard, J.W., & De Palma, M. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat Cell Biol. 2019 Feb;21(2):190-202.
Key findings: We show that two classes of chemotherapeutic agents elicit mammary tumor-derived extracellular vesicles that facilitate the establishment of pulmonary metastasis. This process involves chemotherapy-mediated effects on the protein composition of the extracellular vesicles and their ability to activate a pro-inflammatory and metastasis-supportive response in the lung endothelium.
Highlight in Nat Rev Cancer
News&Opinions in The Scientist
Highlights in F1000Prime
Neubert, N. J.*, Schmittnaegel, M.*, Bordry, N.*, Nassiri, S., Wald, N., Martignier, C., Tillé, L., Hemicsko, K., Damsky, W., Maby El-Hajjami, H., Klaman, I., Danenberg, E., Ioannidou, K., Kandalaft, L., Coukos, G., Hoves, S., Ries, C. H., Fuertes Marraco, S. A., Foukas, P. G., & De Palma, M.§, Speiser, D.E.§ T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci Transl Med. 2018 Apr 11;10(436), pii: eaan3311.
Key findings: We show that activated T cells elicit an immunosuppressive response in melanoma that involves the induction of CSF1 and the recruitment of macrophages. High infiltration of both T cells and macrophages in human melanoma associates with poor response to PD1 immune checkpoint blockade. Elimination of macrophages unleashes the therapeutic potential of PD1 blockade in experimental melanoma models.
Highlight in ACIR.org
Highlight in Cancer Immunol Res
Squadrito, M.L., Cianciaruso, C., Hansen, S.K., & De Palma, M. EVIR: chimeric receptors that enhance dendritic cell cross-dressing with tumor antigens. Nat Methods. 2018 Mar;15(3):183-186.
Key findings: In this article we describe a new chimeric receptor, termed EVIR, with endows dendritic cells with the ability to uptake extracellular vesicles released from the patient’s own tumor and to present pre-formed MHCI/tumor antigens to the immune system, without manipulation of tumor antigens ex vivo. EVIR-engineered dendritic cells may represent a new class of tumor vaccine for personalized therapeutic applications.
Keklikoglou, I., Kadioglu, E., Bissinger, S., Langlois, B., Bellotti, A., Orend, G., Ries, C.H., & De Palma, M. Periostin limits tumor response to VEGFA inhibition. Cell Rep. 2018 Mar;22(10):2530-2540.
Key findings: We show that tumor resistance to VEGFA inhibition (a clinically approved anti-angiogenic treatment) is dependent on periostin, a matricellular protein expressed by stromal cells. Periostin orchestrates VEGFA-independent tumor angiogenesis, in part, by recruiting pro-angiogenic macrophages.
De Palma, M., Biziato, D., & Petrova, T.V. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017 Aug;17(8):457-474.
Key findings: A review that illustrates the complex regulation of angiogenesis by the tumor microenvironment.
Schmittnaegel, M.*, Rigamonti, N.*, Kadioglu, E., Cassará, A., Wyser Rmili, C., Kiialainen, A., Kienast, Y., Mueller, H.-J., Ooi, C.-H., Laoui, D., & De Palma, M. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med. 2017 Apr 12;9(385), pii: eaak9670.
Key findings: This study shows that optimized regimens of anti-angiogenic drugs targeting angiopoietin-2 and VEGFA elicit anti-tumor immunity in experimental cancer models. This involves effects on both the tumor blood vessels and intra-tumoral phagocytes, which fosters cytotoxic T cell activation and extravasation to the tumors. Concurrently, the therapeutic benefits are tempered by the adaptive induction of the immune checkpoint ligand PDL1 in vascular endothelial cells, which can be overcome through pharmacological PD1 inhibition.
Highlight in Nat Rev Clin Oncol
Highlight in Nat Rev Cancer
Highlight in Nat Rev Drug Discov
News in Cancer Research UK
Baer C*, Squadrito ML*, Laoui D, Thompson D, Hansen SK, Kiialainen A, Hoves S, Ries CH, Ooi C-H, & De Palma M. Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumor immunity. Nat Cell Biol. 2016 Jul;18(7):790-802.
Key findings: This study shows that suppressing microRNA activity in tumor-associated macrophages (TAMs) abates their immunosuppressive functions and prompts recruitment and activation of T cells in the tumors. TAM reprogramming enabled tumor eradication by PD1 checkpoint blockade or CD40 agonistic antibodies. These findings indicate that microRNA activity opposes immunostimulatory TAM activation, with potential therapeutic implications.
News & Views by Lee and Biswas (Nat Cell Biol)
Highlight in Natural History Magazine
Highlight in Biomedical Computation Review