Kari Vaahtomeri's research while affiliated with University of Helsinki and other places

Publications (35)

Article
Full-text available
Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor-3 (VEGFR3), encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, t...
Article
Purpose: Mutations in STK11 (LKB1) occur in 17% of lung adenocarcinoma (LUAD) and drive a suppressive (cold) tumor immune microenvironment (TIME) and resistance to immunotherapy. The mechanisms underpinning the establishment and maintenance of a cold TIME in LKB1-mutant LUAD remain poorly understood. In this study, we investigated the role of the...
Article
Full-text available
Gradients of chemokines and growth factors guide migrating cells and morphogenetic processes. Migration of antigen-presenting dendritic cells from the interstitium into the lymphatic system is dependent on chemokine CCL21, which is secreted by endothelial cells of the lymphatic capillary, binds heparan sulfates and forms gradients decaying into the...
Article
During the growth of various cancers, primary tumors can escape anti-tumor immune responses of their host and eventually disseminate into distant organs. Peritumoral lymphatic vessels connect the primary tumor to lymph nodes, facilitating tumor entry into lymph nodes, systemic circulation, and metastasis. Lymph node metastases that occur frequently...
Article
Full-text available
Lymphatic endothelial cells (LECs) release extracellular chemokines to guide the migration of dendritic cells. In this study, we report that LECs also release basolateral exosome-rich endothelial vesicles (EEVs) that are secreted in greater numbers in the presence of inflammatory cytokines and accumulate in the perivascular stroma of small lymphati...
Article
Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast-specific deletion of Lk...
Article
Lymphatic vessels are important for tissue fluid homeostasis, lipid absorption, and immune cell trafficking and are involved in the pathogenesis of several human diseases. The mechanisms by which the lymphatic vasculature network is formed, remodeled, and adapted to physiological and pathological challenges are controlled by an intricate balance of...
Data
Timelapse TIRF microscopy of 5μM ionomycin treated CCL21-mCherry (white) expressing single LEC. Frames were recorded every 0.05’’. White arrows indicate 4 secretion events at 1, 2, 3 and 4 seconds. See Figure 3A. Scale bar is 2 μm.
Data
Movie S6. Endothelial Ca Signaling Is Necessary for DC Transmigration through CCL21ΔC-mCherry Expressing LEC Monolayers, Related to Figure 4 Time-lapse phase contrast microscopy of DCs layered on control or 10μM BAPTA-AM treated CCL21-mCherry or CCL21ΔC-mCherry expressing LEC monolayers. Frames were recorded every 20’’. See Figure 4F. Scale bar is...
Data
Movie S3. Cortical Actin Meshwork Restricts CCL21 Vesicle Motility, Related to Figure 3 Time-lapse TIRF microscopy of CCL21-mCherry (red) and Lifeact-EGFP (green) expressing control or 500ng/ml latrunculin B treated LEC. White arrows indicate CCL21-mCherry vesicles, which move similarly to 30 cortical actin meshwork (green). Frames were recorded e...
Data
Time-lapse TIRF microscopy of control or 500nM nocodazole treated CCL21ΔC-mCherry (red) and EGFP-tubulin α (green) expressing LEC. Frames were recorded every 1’’. White arrows indicate 2 examples of CCL21-mCherry positive vesicle gliding along a microtubule at 36’’ and 98’’. See Figure 2D. Scale bar is 2μm.
Data
Movie S4. DC Transmigration through LEC Monolayer In Vitro Is CCL21-Dependent, Related to Figure S2 Time-lapse phase contrast microscopy of DCs layered on non-infected or CCL21-mCherry, CCL21ΔC-mCherry or CCL21ΔN-mCherry expressing LECs. Frames were recorded every 20’’. Every second frame is shown in the video. See Figure S2D for quantification. S...
Data
Time-lapse epifluorescence microscopy of 10μM Oregon Green BAPTA-AM treated LEC monolayer (green) and either approaching (red, video on the left) or transmigrating DC (video on the right). Frames were recorded every 2.2’’. White arrows indicate LECs displaying Ca transients. See Figure 4D. Scale bar is 10μm.
Article
Full-text available
Trafficking cells frequently transmigrate through epithelial and endothelial monolayers. How monolayers cooperate with the penetrating cells to support their transit is poorly understood. We studied dendritic cell (DC) entry into lymphatic capillaries as a model system for transendothelial migration. We find that the chemokine CCL21, which is the d...
Article
Navigation of cells along gradients of guidance cues is a determining step in many developmental and immunological processes. Gradients can either be soluble or immobilized to tissues as demonstrated for the haptotactic migration of dendritic cells (DCs) toward higher concentrations of immobilized chemokine CCL21. To elucidate how gradient characte...
Article
Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independent...
Article
Germline mutations in tumor suppressor kinase Lkb1 predispose to Peutz-Jeghers syndrome (PJS), with highly penetrant gastrointestinal polyposis and increased cancer risk. PJS polyps display abnormal growth of both stromal and epithelial cells. We have identified clonally expanding fibroblasts as the drivers of tumorigenesis in PJS mouse models by u...
Article
Full-text available
To induce adaptive immunity, dendritic cells (DCs) migrate through afferent lymphatic vessels (LVs) to draining lymph nodes (dLNs). This process occurs in several consecutive steps. Upon entry into lymphatic capillaries, DCs first actively crawl into downstream collecting vessels. From there, they are next passively and rapidly transported to the d...
Data
Supplementary Figures 1-14 and Supplementary Tables 1-4
Article
Full-text available
AMP-activated protein kinase (AMPK) inhibits several anabolic pathways such as fatty acid and protein synthesis, and identification of AMPK substrate specificity would be useful to understand its role in particular cellular processes and develop strategies to modulate AMPK activity in a substrate-specific manner. Here we show that SUMOylation of AM...
Article
While the role of LKB1 mutations in the Peutz-Jeghers polyposis syndrome (PJS) is uncontroversial, the originating cell type remains unclear as Lkb1 mutations in both epithelial cells and stromal smooth muscle cells (SMCs) have been proposed as tumor drivers. Since SMCs do not represent a major fraction of stromal cells in polyps, altered signaling...
Article
Lkb1 has emerged as an important tumor suppressor gene in both sporadic and hereditary cancer. Inactivating germline mutations in the LKB1 gene underlie familial Peutz-Jeghers Syndrome (PJS), a cancer-prone disorder characterized by predisposition to gastrointestinal polyposis. Targeted disruption of Lkb1 in mesenchymal smooth muscle cells was suff...
Article
Actin stress fiber assembly and contractility in nonmuscle motile cells requires phosphorylation of myosin regulatory light chain (MLC). Dephosphorylation and disassembly are mediated by MLC phosphatase, which is targeted to actin fibers by the association of its regulatory subunit MYPT1 with myosin phosphatase Rho-interacting protein (MRIP). In th...
Article
The LKB1 tumor suppressor gene is frequently mutated in sporadic lung adenocarcinomas and cervical cancers and germline mutations are causative for Peutz-Jeghers syndrome characterized by gastrointestinal polyposis. The intracellular LKB1 kinase is implicated in regulating polarity, metabolism, cell differentiation, and proliferation - all function...
Article
p27Kip1 (p27) tumour suppressor protein is regulated by multiple mechanisms including its turnover, localization and complex formation with its key targets, cyclin-dependent kinases (CDK) and cyclins. We have earlier shown that p27 exists in cells in a form that lacks cyclin/CDK interactions (hence non-CDK, p27(NCDK)) but the nature of p27(NCDK) ha...
Article
Full-text available
The mobilization of metabolic energy from adipocytes depends on a tightly regulated balance between hydrolysis and resynthesis of triacylglycerides (TAGs). Hydrolysis is stimulated by beta-adrenergic signalling to PKA that mediates phosphorylation of lipolytic enzymes, including hormone-sensitive lipase (HSL). TAG resynthesis is associated with hig...
Article
Full-text available
Inactivating mutations of the tumor-suppressor kinase gene LKB1 underlie Peutz-Jeghers syndrome (PJS), which is characterized by gastrointestinal hamartomatous polyps with a prominent smooth-muscle and stromal component. Recently, it was noted that PJS-type polyps develop in mice in which Lkb1 deletion is restricted to SM22-expressing mesenchymal c...
Article
Inactivation of the tumor suppressor kinase Lkb1 in mice leads to vascular defects and midgestational lethality at embryonic day 9-11 (E9-E11). Here, we have used conditional targeting to investigate the defects underlying the Lkb1(-/-) phenotype. Endothelium-restricted deletion of Lkb1 led to embryonic death at E12.5 with a loss of vascular smooth...
Article
Full-text available
Germline mutations in STK11 (also known as LKB1) are found in individuals with Peutz-Jeghers syndrome (PJS) manifesting with gastrointestinal polyps that contain a prominent stromal component. Epithelia in polyps of Stk11(+/-) mice can retain a functional copy of Stk11 (refs. 2,3), and loss of heterozygosity is not an obligate feature of human poly...
Article
Inactivating germline mutations in the LKB1 gene underlie Peutz-Jeghers syndrome characterized by hamartomatous polyps and an elevated risk for cancer. Recent studies suggest the involvement of LKB1 also in more common human disorders including diabetes and in a significant fraction of lung adenocarcinomas. These observations have increased the int...
Article
Germline mutations of the LKB1 tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS), with a predisposition to cancer. LKB1 encodes for a nuclear and cytoplasmic serine/threonine kinase, which is inactivated by mutations observed in PJS patients. Restoring LKB1 activity into cancer cell lines defective for its expression results in a G(1) cell...

Citations

... CCL21 contains a highly positively charged C-terminus, which confers binding to glycosaminoglycan-containing heparan sulfates (HS-GAGs) present on the surface of LECs and other cell types.75,76 However, also other negatively charged molecules, including LECexpressed podoplanin77 and BM/ECM components have been shown or suggested to bind CCL21.78,79 Confocal imaging performed in ear skin revealed that most CCL21 is stored intracellularly in the trans-Golgi network.72,80 ...
... Tumor lymphangiogenesis is a process that newly formed lymphatic vessels sprout from pre-existing ones of a growing tumor. This process is vital for tumor progression, where it forms antitumor immunity, and provides physical routes for cell dissemination [1,2]. Newly formed lymphatic vessels substantially increase the area of lymphatic-tumor interface, thereby contributing to the invasion and metastasis of primary tumors to sentinel lymph nodes (LNs) [3,4]. ...
... Exos from RegDC (RegDC-Exos) suppress the maturation of DCs and promote the recruitment of Treg cells, resulting in the inhibition of bone resorptive cytokines and reduction in osteoclastic bone loss [72]. Exos from lymphatic endothelial cells (LEC-Exos) promote the directional migration of human DCs in complex tissue environments in a CX3CL1/fractalkine-dependent fashion [73]. ...
... Moreover, silencing of YTHDF2 induced by HIF-2α could enhance the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expression of interleukin-11 (IL-11) and serpin peptidase inhibitor clade E member 2 (Serpin E2) [50]. IL-11 could promote STAT3 activation and inflammatory cancer progression in an autocrine manner, and Serpin E2 could promote the progression of invasion and metastasis by reprogramming the tumor vascular system [99]. The results revealed that HIF-2α could induce hypoxia to reduce the expression of YTHDF2. ...
... In the hierarchical lymphatic vascular network, the blind-ended lymphatic capillaries have discontinuous button-like cell-cell junctions and a thin and loose basement membrane, permitting efficient absorption of fluid from the interstitial space in tissues. This fluid, lymph, is transported back to the blood circulation via specialized collecting lymphatic vessels, which have a basement membrane and smooth muscle cell (SMC) coverage, endothelial cell zipper junctions, as well as valves to prevent lymph leakage and backflow (8,9). Vascular endothelial growth factor C (VEGF-C), and its receptor VEGF receptor-3 (VEGFR3) and co-receptor neuropilin 2 (Nrp2) in lymphatic endothelial cells (LECs), are the major drivers of lymphangiogenesis in embryos and their deficiency leads to failure of lymphatic vessel development and embryonic lethality (10, 11). ...
... The phenotype and function of highly motile DCs is influenced by co-stimulatory molecules (CD80, CD86), chemokine receptors such as CCR7 and cell adhesion molecules (integrins, ICAM-1 and VCAM-1) (40)(41)(42)(43). It has been well established that the interaction between CC chemokine receptor 7 (CCR7) upregulated on activated DCs and its ligand CC chemokine ligand 21 (CCL21) expressed by lymphatic endothelial cells (LECs) is essential for directional DC migration towards the lymph nodes (44)(45)(46). Upon entry to the LN, DCs use the C-type lectin CLEC-2 to migrate through the fibroblastic reticular network to reach the paracortex to stimulate the T cells (47)(48)(49)(50). Secondary lymphoid tissues are structurally specialised to facilitate effective adaptive immune responses; however, the microenvironment of the tumourdraining lymph nodes (TDLNs) can be immune-suppressed in cancer patients and can display low DC count, defects in DC development, low levels of costimulatory molecules or accumulation of immature T cells (51,52). ...
... Consistent with a previous study on murine chemokines, we found that a stable gradient was established after about two to three hours for CCL19-S6 Dy549P1 and CCL21-S6 Dy549P1 , whereas gradient formation of dextran FITC was not temporally affected (13). The steep gradient shape of CCL21-S6 Dy549P1 in our 3D matrix mimics the fast decay of the murine CCL21 gradient away from the lymphatic vessels reported in the dermis (8,26). We further show that gradients formed by two ligands for CCR7 are of a different shape and point to a limited meaningfulness of using dextran as surrogate molecule to characterize chemokine gradients. ...
... Although the exact mechanisms of transfusion-related immunomodulation are not still understood, possible the mechanisms include suppression of cytotoxic cells and monocyte/macrophages activity (37). It was already demonstrated that hemolysis alters actin cytoskeleton remodeling, triggering decreased phagocytic capacity (53). Corroborating, our findings have shown that stored RBC-EVs presented high amounts of heme, which was transferred to monocytes, triggering acute ROS production dependently and independently of TLR4, suggesting a dual role of RBC-EVs in monocytes activation. ...
... The expression of C-C chemokine receptor (CCR) type 7 increases on the surface of activated DCs, which migrate according to the concentration gradient of C-C chemokine ligand (CCL) type 21 secreted by LECs. Furthermore, after reaching the lymphatic vessels, activated DCs invade them using intercellular adhesion molecule 1 and/or vascular cell adhesion molecule 1 and flow into the draining lymph nodes [54][55][56][57][58]. In lymph nodes, naïve CD4+ T cells are activated by DCs, and increase the expression of cutaneous leukocyte antigen (CLA), CCR4, CCR9, and CCR10. ...
... In contrast, PIAS2α inhibits PI3K/AKT signaling through sumoylation of the tumor suppressor PTEN, thereby decreasing its degradation and inhibiting PI3K/AKT signaling through its phosphatase activity [153]. [171,172,[191][192][193] PIAS4 adrenocortical, mesothelioma, thyoma [165] breast [176,194,195] CRC [196] GC [197] HCC [198] lung [199,200] ovarian [201] pancreas [202] Others CBX4 bladder, cholangiocarcinoma, EC, esophageal, melanoma, mesothelioma, pancreatic, renal, sarcoma, thyoma, thyroid [165] breast [203] cervical [204,205] Not all proteins promoting sumoylation of specific targets, and, thereby, described as putative ligases, have been properly demonstrated to display such an enzymatic activity at the biochemical level. Furthermore, all of them have additional functions independent of SUMO. ...