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Bocci, Matteo Growth factor signaling in the breast tumor microenvironment Bocci, Matteo 2018 Document Version: Publisher's PDF, also known as Version of record Link to publication Citation for published version (APA): Bocci, M. (2018). Growth factor signaling in the breast tumor microenvironment. Lund University: Faculty of Medicine. 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LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 Growth factor signaling in the breast tumor microenvironment MATTEO BOCCI DEPARTMENT OF LABORATORY MEDICINE | FACULTY OF MEDICINE | LUND UNIVERSITY AN ECOLABEL 3041 0903 ryck, Lund 2018 NORDIC SW Printed by Media-T Department of Laboratory Medicine Lund University, Faculty of Medicine 196977 Doctoral Dissertation Series 2018:129 ISBN 978-91-7619-697-7 789176 ISSN 1652-8220 9 Growth factor signaling in the breast tumor microenvironment Matteo Bocci DOCTORAL DISSERTATION by due permission of the Faculty of Medicine, Lund University, Sweden. To be defended at the main lecture hall, Medicon Village, Lund. Friday, 16th November at 09:30 AM. Faculty opponent Professor Morag Park Rosalind & Morris Goodman Cancer Research Centre Departments of Biochemistry, Medicine and Oncology McGill University, Montreal, Canada Organization Document name LUND UNIVERSITY Doctoral dissertation Faculty of Medicine Date of issue Translational Cancer Research 16 Novmber, 2018 Author: Matteo Bocci Sponsoring organization: NA Title and subtitle Growth factor signaling in the breast tumor microenvironment Abstract Cancer represents a collection of malignancies characterized by an aberrant expansion of cells. This unrestrained growth is the result of the acquisition of several pro-survival features and the evasion of cellular fail-safe mechanisms, collectively known as the hallmarks of cancer. In the clinical setting, disease management has heavily relied on the sole targeting of malignant cells but, except for rare cases, monotherapy regimens showed insufficient antitumor activity. Indeed, translational and clinical studies revealed that cancer cells almost invariably adapt to treatment, mainly through acquisition of additional (epi)mutations and/or clonal diversification and activation of bypass signaling pathways. In parallel, characterization of the malignant mass exposed the existence of other (non- transformed) cell types and non-cellular constituents, with specialized functions and potentially different origins, jointly reffered to as the tumor stroma. This local microenvironment is educated by and coevolves with the cancer cells by engaging in an intricate network of communication that plays a fundamental role in the establishment, progression and malignization of a tumor, as well as modulating the response to treatment. The stroma comprises the endothelial cells and pericytes that compose the vasculature, fibroblasts, immune cells and the extracellular matrix. Therefore, the genetic make-up of polyclonal tumors and the composition of the microenvironment define the genomic, spatial and functional diversity of each tumor, also at the metastatic site. In agreement with this, the concept of intratumoral heterogeneity denotes a key aspect that has been increasingly recognized, although not fully implemented, in personalized medicine. Moreover, recent efforts have started to address the systemic changes instigated by the tumor mass –including metabolism– and how these influence the survival/dormancy, the colonization and the metastatic growth of disseminated cancer cells. In the papers included in this thesis, we made use of experimental breast cancer models to deepen our understanding of the tumor milieu and its clinical implications. Paper I reports the results of the preclinical trials of a compound that was designed to block activin receptor-like kinase (ALK)1, a protein involved in the formation of the blood vessels. Experimental models showed promising inhibition of tumor growth and marked reduction of the metastatic disease. In paper II, we analyzed how ALK1 communicates in different tumors in order to determine a set of characteristics that might help to predict which patients could benefit from ALK1-blocking therapy. Moreover, we discovered that the presence of ALK1 in tumor blood vessels influences the presence and function of the immune cells. In paper III, we define a novel therapeutic opportunity for the basal subtype of breast cancer, for which only surgery, radio- and chemotherapy are currently available. We identified the specific role of PDGF-C, that is released by tumor cells to activate fibroblasts. This communication loop maintains the tumor cells in a more aggressive state and makes them resistant to treatment. Thus, by blocking PDGF-C, tumor cells transform to a less aggressive luminal type and become sensitive to endocrine therapy, which can be used to limit the development of the tumor mass. Finally, paper IV gives us information about the diversity of the cells within the fibroblast population. By using a state of the art technology, we increased the resolution at which we are able to distinguish the function of each individual fibroblast isolated from a tissue, and match it with a specific cell-of-origin. Taken together, the use of mouse models of cancer allows us to reproduce the complexity of human tumors, and delineate how these cellular relationships are shaped and maintained during tumor development. Our data illustrate the value of impinging on the crosstalk between tumor cells and other components of the tumor mass to develop novel therapeutic strategies for the clinical management of breast cancer. Key words: Breast cancer, tumor microenvironment, angiogenesis, cancer-associated fibroblast, PDGF-C, ALK1 Classification system and/or index terms (if any): NA Supplementary bibliographical information: NA Language: English ISSN and key title: 1652-8220 ISBN: 978-91-7619-697-7 Lund University, Faculty of Medicine Doctoral Dissertation series 2018:129 Recipient’s notes: NA Number of pages Price: NA Security classification: NA I, the undersigned, being the copyright owner of the abstract of the above-mentioned dissertation, hereby grant to all reference sources permission to publish and disseminate the abstract of the above-mentioned dissertation. Signature Date2FWREHU Growth factor signaling in the breast tumor microenvironment Matteo Bocci Cover photo by Inês Bravo: Multiculturalism and integration - cancer edition. Copyright Matteo Bocci Faculty of Medicine Department of Laboratory Medicine Lund University, Faculty of Medicine, Doctoral Dissertation Series 2018:129 ISBN 978-91-7619-697-7 ISSN 1652-8220 Printed in Sweden by Media-Tryck, Lund University, Lund 2018 &$" $ *-))* *+,-./01 " % ! !" # ###% $%!% To Roberta, “il mio turchese” “And once the storm is over, you won’t even remember how you made it through, how you managed to survive. You won’t even be sure, whether the storm is really over. But one thing is certain. When you come out of the storm, you won’t be the same person who walked in. That’s what this storm’s all about”. Haruki Murakami – Kafka on the shore “Some natural tears they dropped, but wiped them soon; The world was all before them, where to choose their place of rest, and Providence their guide They, hand in hand, with wandering steps and slow, Through Eden took their solitary way”. John Milton – Paradise lost Table of Contents List of original papers ............................................................................................... 9 Abbreviations ......................................................................................................... 11 Acknowledgements ................................................................................................ 17 Popular science summary ....................................................................................... 23 Sintesi scientifica a scopo divulgativo ................................................................... 25 Abstract .................................................................................................................. 27 The tumor microenvironment ................................................................................. 29 Mesenchymal cells ....................................................................................... 31 Cancer-associated fibroblasts .............................................................. 31 Pericytes .............................................................................................. 36 Vasculature ..................................................................................................
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