Charlotte Rolny's Group
Tumor immuno editing by semaphorins. Our research focuses on inflammation mediated tumor growth and metastatic dissemination. More specifically, we are interested in the involvement of semaphorins in regulating tumor related inflammation. If the regulatory role of these molecules can be assessed, it will be possible to develop new therapies.
Strong evidence links cancer-associated inflammation with tumor growth and spreading of tumor cells to secondary organs (metastatic dissemination). Tumor associated macrophages (TAMs)- a specific type of immune cells- secrete a variety of growth factors that stimulate formation of new tumor blood vessels (angiogenesis). However, tumor blood vessels are often leaky and dysfunctional, which contributes to metastasis. TAMs also produce immune suppressive substances that inhibit activation of immune cells that are involved in anti-tumoral activity. Thus by skewing pro-angiogenc/immune suppressive TAMs towards an angiostatic/pro-inflammatory phenotype, tumor vessels can be normalized (Figure 1 and 2) and metastasis restrained while tumor growth is inhibited. In conclusion, to regulate tumor immunity offers and attractive therapeutic strategy to inhibit tumor progression.
The role of immune sempahorins on tumor progression
We study semaphorins, a group of proteins that regulate the immune response. The role of semaphorins appears contradictory; while certain semaphorins recruit and activate immune cells, others deactivate and repulse immune cells. Our aim is to determine the mechanisms underlying semaphorin mediated immuno editing and its affect on tumor growth. Thus, the knowledge about the regulatory role of semaphorins may be used to develop novel anti-tumoral therapies.
Semaphorin mediated regulation of metastatic dissemination: the involvement of hematopoietic cells.
We have previously been able to pinpoint that administration of SEMA3A by lenti-viral mediated gene therapy reduce tumour growth, tumour vessel formation, lymphangiogenesis and metastatic dissemination SEMA3A efficiently inhibited tumour growth by inducing endothelial apoptosis, impairing vessel function and increasing tumour hypoxia and necrosis. Intriguingly, even though SEMA3A induced a hypoxic microenvironment that favours metastatic dissemination, were efficiently inhibited in a neuropilin-1 (SEMA3A receptor)-dependent manner. Thus, inhibition of SEMA3A has showed to be an attractive strategy that concomitantly target both endothelial cells and prevent tumor cell spreading. Intriguingly, neuropilin 1 is not only expressed by tumor cells and endothelial cell but also on a subset of haematopoietic cells e.g. macrophages and T cells. We are currently investigating the role of SEMA3A and other immune semaphorins in inflammations mediated tumor progression.
The role of microglia in Glioma
Glioma is usually treated by surgery, however due to the invasive properties of gliomas, this treatment is rarely successful. Thus, to constrain local invasive properties of gliomas is an attractive therapeutic strategy. Microglia (resident macrophage of the brain) is one of the most plastic cells in the brain; it has recently been shown that M2 polarized (pro-tumoral) microglia correlates with high-grade glioma tumor malignancy. We are now interested investigating the role of microglia and inflammatory monocytes in glioma tumor progression. Moreover, we will investigate the involvement of semaphorins (axon guidance molecules) in glioma tumor progression.
Charlotte Rolny, Associate Professor, Group leader
Dennis Alexander Agardy, Research fellow
Majken Wallerius, PhD student
Margarita Bartish, PhD student
Tatjana Wallmann, PhD student
Emma Nygren, Master student
Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages.
Cancer Res. 2016 06;76(11):3166-78
Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq.
Science 2015 Mar;347(6226):1138-42
The role of immune semaphorins in cancer progression.
Exp. Cell Res. 2013 Jul;319(11):1635-43
Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-γ.
Eur. J. Immunol. 2013 Jan;43(1):249-57
Genetic deficiency in plasma protein HRG enhances tumor growth and metastasis by exacerbating immune escape and vessel abnormalization.
Cancer Res. 2012 Apr;72(8):1953-63
Systemic and targeted delivery of semaphorin 3A inhibits tumor angiogenesis and progression in mouse tumor models.
Arterioscler. Thromb. Vasc. Biol. 2011 Apr;31(4):741-9
Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice.
J. Clin. Invest. 2010 Aug;120(8):2684-98
A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils.
Blood 2010 Sep;116(11):1924-31
Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.
Cell 2010 Apr;141(1):178-90
The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment.
J. Exp. Med. 2008 May;205(5):1155-71