| 1. |
- Bartish, Margarita
(författare)
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War and peace in the tumor microenvironment : tumor-associated cells as facilitators or adversaries during tumor development
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The tumor microenvironment, including immune cells, fibroblasts and vasculature, profoundly affects tumor development by initially opposing, but eventually facilitating tumor growth, vascularization and spread. Though corrupted by the growing tumor, such cells remain non-transformed and thus, with proper cues, are possible to direct toward their physiological anti-tumor function. Understanding the mechanisms by which the tumor microenvironment is shaped, before and during tumor growth, has been the principal aim of this thesis. In paper I, we demonstrate that the composition of tumor-associated macrophages (TAMs) can be modulated by selective proliferation of TAM subsets. We identify SEMA3A as a factor potentiating such selective proliferation of anti-tumor TAMs. In paper II we extend the study of SEMA3A’s effect on tumor immunity by showing that it can functionally alter the phenotype of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). As a consequence of its effects on TAMs and PMN-MDSCs, the tumor microenvironment is infiltrated by activated cytotoxic lymphocytes which act to obstruct tumor growth. In paper III we show that regulation of mRNA translation shapes the phenotype of TAMs as they become increasingly pro-tumor during tumor growth. We further show that transcripts translationally activated during tumor growth in TAMs were regulated similarly upon M2- polarization of macrophages in vitro. Selective inhibition of the MNK2/phospho-eIF4E pathway, which impinges on mRNA translation, functionally altered in vitro M2-polarized macrophages toward a pro-inflammatory phenotype. This suggests that modulation of mRNA translation is a potential target in TAM-based anti-tumor therapies. We further emphasize the importance of mRNA translation in regulating gene expression in the microenvironment in paper IV, where we show changes in its efficiency to drive cancer- associated gene expression alterations in the stroma of patients with chronic obstructive pulmonary disease (COPD). Depending on the lung function, two distinct gene expression programs were discovered. These were enriched for proteins previously identified in fibroblast secretomes that promoted cancer initiation in animal models, highlighting the involvement of non-transformed cells in neoplastic transformation. In paper V, we show that class switch junctions in B cells from patients with BRCA1 mutations display decreased use of non-homologous end joining pathway in favor of the alternative end-joining pathway. This implicates a role for BRCA1 in maintaining genome stability and tumor suppression outside of its recognized role in mediating homologous recombination during cell division.
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| 2. |
- Björkman, Andrea, et al.
(författare)
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Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells.
- 2015
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 112:7, s. 2157-2162
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1's function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.
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| 3. |
- Sjöberg, Elin, et al.
(författare)
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A Novel ACKR2-Dependent Role of Fibroblast-Derived CXCL14 in Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer
- 2019
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 25:12, s. 3702-3717
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Fibroblasts expressing the orphan chemokine CXCL14 have been previously shown to associate with poor breast cancer prognosis and promote cancer growth. This study explores the mechanism underlying the poor survival associations of stromal CXCL14.Experimental Design: Tumor cell epithelial-to-mesenchymal transition (EMT), invasion, and metastasis were studied in in vitro and in vivo models together with fibroblasts overexpressing CXCL14. An approach for CXCL14 receptor identification included loss-of-function studies followed by molecular and functional endpoints. The clinical relevance was further explored in publicly available gene expression datasets.Results: CXCL14 fibroblasts stimulated breast cancer EMT, migration, and invasion in breast cancer cells and in a xenograft model. Furthermore, tumor cells primed by CXCL14 fibroblasts displayed enhanced lung colonization after tailvein injection. By loss-of function experiments, the atypical G-protein-coupled receptor ACKR2 was identified to mediate CXCL14-stimulated responses. Downregulation of ACKR2, or CXCL14-induced NOS1, attenuated the pro-EMT and migratory capacity. CXCL14/ACKR2 expression correlated with EMT and survival in gene expression datasets. 'Conclusions: Collectively, the findings imply an autocrine fibroblast CXCL14/ACKR2 pathway as a clinically relevant stimulator of EMT, tumor cell invasion, and metastasis. The study also identifies ACKR2 as a novel mediator for CXCL14 function and thereby defines a pathway with drug target potential.
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| 4. |
- Wallerius, Majken, et al.
(författare)
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Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages
- 2016
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:11, s. 3166-3178
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Tidskriftsartikel (refereegranskat)abstract
- Accumulation of tumor-associated macrophages (TAM) correlates with malignant progression, immune suppression, and poor prognosis. In this study, we defined a critical role for the cell-surface guidance molecule SEMA3A in differential proliferative control of TAMs. Tumor cell-derived SEMA3A restricted the proliferation of protumoral M2 macrophages but increased the proliferation of antitumoral M1, acting through the SEMA3A receptor neuropilin 1. Expansion of M1 macrophages in vivo enhanced the recruitment and activation of natural killer (NK) cells and cytotoxic CD8(+) T cells to tumors, inhibiting their growth. In human breast cancer specimens, we found that immunohistochemical levels of SEMA3A correlated with the expression of genes characteristic of M1 macrophages, CD8(+) T cells, and NK cells, while inversely correlating with established characters of malignancy. In summary, our results illuminate a mechanism whereby the TAM phenotype is controlled and identify the cell-surface molecule SEMA3A as a candidate for therapeutic targeting.
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