Biology subjects

Salmi, M.

Publications and source records attributed to Salmi, M..

14 recordsLinked to original sources

bioRxiv2026

Single-Cell Profiling Reveals Innate Lymphoid Cells and OX40 Activation in Breast Cancer-Related Lymphedema

ABSTRACT Breast cancer-related lymphedema (BCRL) is a severe complication affecting up to 40% of breast cancer survivors. Stage II or chronic disease stages are characterized by upper-limb edema, fibrotic adipose tissue accumulation, pain, and recurrent infections. Despite its clinical burden, BCRL lacks effective pharmacological therapies and the molecular mechanisms driving disease progression remain poorly understood. To better define the regulatory mechanisms underlying chronic BCRL, we performed transcriptomic and quantitative analyses of stromal vascular fraction cells (SVF or non-adipose cell fraction) in BCRL-derived subcutaneous adipose tissue. CD45+ immune cells from stage II BCRL were compared with those from healthy lean and obese adipose tissue controls. Although our analyses identified multiple leukocyte populations, we focused primarily on innate lymphoid cells (ILCs), particularly ILC2 and ILC3 subsets, which were more abundant and active in BCRL tissues. Bioinformatics analysis of cell-cell communication positioned ILCs as central immune-regulatory hubs in BCRL through inflammatory and tissue-remodeling pathways, including connections to IL2, OX40, KIT, and LT signaling. Strong bidirectional communication between ILCs and regulatory T cells via OX40 signaling was uniquely detected in BCRL. Consistent with these findings, protein-based analyses confirmed increased inflammatory mediators and enrichment of the OX40 and OX40L co-stimulatory pair in BCRL tissues. Taken together, our findings identify OX40-dependent ILC-signaling as a novel regulatory program supporting chronic inflammation and pathological tissue remodeling in BCRL.

immunology↗

bioRxiv2026

Pancreatic cancer cells breach endothelial barriers through protrusion-driven invasion or endothelial retraction

Extravasation, the exit of circulating cancer cells from blood vessels, is a critical yet poorly understood step in metastatic dissemination. Here we show that pancreatic ductal adenocarcinoma (PDAC) cells can breach endothelial barriers through two mechanistically distinct modes of extravasation. MIA PaCa-2 cells breach endothelial junctions via filopodia-like protrusions, enabling access to and spread across the basal extracellular matrix (ECM). By contrast, AsPC-1 cells remain rounded atop the endothelium and cross the barrier by triggering rapid retraction of neighbouring endothelial cells. These distinct extravasation modes were also observed in zebrafish larvae. In the mouse lung, AsPC-1 cells arrest, survive, induce endothelial detachment from the basal lamina, and extravasate through this retraction mechanism before metastatic outgrowth. Mechanistically, AsPC-1-secreted factors are sufficient to destabilise endothelial monolayers, and AsPC-1 cells also induce endothelial apoptosis; however, blocking apoptosis does not prevent barrier disruption. By contrast, treatment with saracatinib, a Src-family kinase inhibitor, protects endothelial barriers, limits early vascular disruption in the lung, and delays metastatic outgrowth. Together, these findings reveal that PDAC cells can extravasate via mechanistically distinct routes, suggesting that effective anti-metastatic strategies may need to target multiple modes of endothelial barrier breach rather than a single pathway.

cell biology↗

bioRxiv2025

CD74 regulates antitumor immunity in melanoma by reprogramming dendritic cell immunogenicity and migration

Metastatic cutaneous melanoma remains a major therapeutic challenge, as many patients fail to respond or relapse following immune checkpoint therapy. The function of CD74, originally described as an MHC-II chaperone and receptor for macrophage migration inhibitory factor, remains poorly understood in tumor immunity. In this study, we show that systemic CD74 deletion in a syngeneic melanoma model significantly delayed tumor growth and reshaped the tumor immune microenvironment, and synergized with immune checkpoint blockade. Tumors in Cd74-/- mice had more effector and memory CD8+ T cells producing IFN-{gamma} and granzyme B than in control mice. Loss of CD74 promoted expansion of migratory cDC1s with elevated MHC-I and CCR7 expression. Cd74-/- professional antigen presenting cells increased cross-priming capacity for tumor-derived antigens in vivo and in vitro. Absence of CD74 induced the expression of CCR7, a key lymph node homing molecule, on cDCs and enhanced their ability to migrate towards the CCL19 ligand in single cell tracking analyses. These findings identify CD74 as a regulator of dendritic cell function and a promising therapeutic target to improve melanoma immunogenicity. One Sentence SummaryCD74 restrains cross-priming and migration capacity of dendritic cells, leading to impaired CD8+ T-cell infiltration and activation in tumor immunity.

immunology↗

bioRxiv2025

CXCL12, SCF, and eotaxin are prognostic serum biomarkers in gastric cancer

Gastric cancer is the fifth most common cancer worldwide and the fifth leading cause of cancer-related death. Its poor prognosis is primarily due to a late diagnosis and a lack of effective treatments for advanced disease. We aimed to identify new prognostic serum biomarkers to aid clinical decision-making. Our patient cohort consisted of 240 individuals who underwent surgery for histologically verified gastric adenocarcinoma in the Department of Surgery, Helsinki University Hospital, between 2000 and 2009. To determine serum protein concentrations of cytokines and growth factors, we utilized Bio-Rads premixed Bio-Plex Pro Human Cytokine 27-plex and 21-plex assay kits. Among the 48 biomarkers analyzed, three emerged as statistically significant prognostic markers for disease-specific survival using the Cox proportional hazards univariate analysis: C-X-C motif chemokine ligand 12 (CXCL12) (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.23-0.63, p<0.001), stem cell factor (HR 0.38, 95%CI 0.19-0.77, p=0.007), and eotaxin (HR 0.57, 95%CI 0.37-0.89, p=0.013). Multivariate survival analysis revealed that, among the 48 biomarkers analyzed, CXCL12 and eotaxin served as independent prognostic markers among gastric cancer patients. The prognostic effect of inflammatory serum biomarkers in gastric cancer could provide new insights into the immunological microenvironment of disease.

pathology↗

bioRxiv2025

CCL5, CLEC11A, IL-7, IL-8, and IL-13: Diagnostic serum biomarkers of gastric cancer identified in a 48-multiplex panel

BackgroundGastric cancer is the fifth most common cancer worldwide and the fifth leading cause of cancer-related death. Its poor prognosis is primarily due to a late diagnosis and a lack of effective treatments for advanced disease. MethodsWe examined a patient cohort comprising 239 individuals who underwent surgery for histologically verified gastric adenocarcinoma in the Department of Surgery at Helsinki University Hospital between 2000 and 2009, comparing them to 48 healthy controls. We measured the serum protein concentrations for 48 different cytokines and growth factors using two of Bio-Rads premixed Bio-Plex Pro Human Cytokine 27-plex and 21-plex assay kits. ResultsFive serum biomarkers were identified as indicative of gastric cancer. Cancer patients had higher serum levels of CLEC11A [odds ratio (OR) 1.16, 95% confidence interval (CI) 1.08- 1.26, p = 0.004], IL-7 (OR 2.73, 95% CI 1.48-5.04, p = 0.014), IL-8 (OR 6.30, 95% CI 2.23-20.0, p = 0.017), and IL-13 (OR 2.67, 95% CI 1.33-5.37, p = 0.041). The CCL5 levels were lower in cancer patients compared with controls (OR 0.30, 95% CI 0.14-0.60, p = 0.014). ConclusionsIn a large cohort of 239 patients, we identified five biomarkers for which serum levels associated with gastric cancer: CCL5, CLEC11A, IL-7, IL-8, and IL-13. High serum levels of CLEC11A have not previously been associated with gastric cancer. Our results provide new support to further explore the effect of these inflammatory molecules and the role they play in gastric cancer. This may help identify novel noninvasive diagnostic methods as well as potential new druggable targets.

pathology↗

bioRxiv2025

Tissue-resident neutrophils serve homeostatic and immunological functions in embryos

Development of neutrophils in the bone marrow and their crucial role in first-line defense are well understood in adults, but remarkably little is known about fetal neutrophils. Here, we analyzed the production, distribution, and functions of neutrophils during embryonic development in the mouse. We discovered that multiple non-hematopoietic steady-state organs harbor substantial numbers of immature and mature neutrophils, many of which are localized to tissue parenchyma outside the vessels. Using single-cell transcriptomic analyses, we revealed the presence of neutrophil progenitors and precursor cells in the blood and even in non-hematopoietic tissues in fetal and newborn mice. Embryonic tissue-resident neutrophils were transcriptionally different from embryonic blood-borne neutrophils and adult neutrophils. We demonstrated, through functional analyses, that embryonic neutrophils proliferated actively, had a high glycolytic capacity, and exhibited distinct diurnal rhythmicity. Embryonic neutrophils displayed lineage-specific innate immune effector functions and were responsive to maternal immunostimulation and immunosuppression. Using a genetic embryonic neutrophil depletion model, we discovered that neutrophils impact the piRNA pathway in the testis. Collectively, our data provides an atlas of the fetal neutrophil landscape and dissects their responses in steady-state. SummaryNon-hematopoietic steady-state tissues harbor extravascular immature and mature neutrophils during fetal development. Embryonic neutrophils are endowed with multiple effector mechanisms and also serve homeostatic roles during tissue development.

immunology↗

bioRxiv2025

Embryonic macrophages in brown adipose tissue are spatially associated with developing nerves

Brown adipose tissue (BAT) is a specialized adipose tissue that produces heat through sympathetic nerve-dependent thermogenesis and influences glucose and triglyceride metabolism, making it a potential target for obesity-related diseases. In mice, interscapular BAT (iBAT) emerges on embryonic days (E)14.5-15.5, with extensive vessel and nerve networks still maturing postnatally. These developmental stages are critical for BAT, impacting long-term BAT function. In adult mice, macrophages regulate sympathetic innervation and thermogenesis. However, research on BAT macrophage characters, ontogeny, and functions in early life is lacking. Using single-cell genomics and proteomics, fate-mapping techniques, and 3D imaging, we analyzed iBAT macrophages during early development. We discovered the presence of fetal liver-derived macrophages as early as E15.5, which are later fully replaced by bone marrow-derived macrophages. Transcriptomics data highlight mononuclear phagocyte subpopulations, from which most express macrophage-associated genes (Adgre1, Fcgr1, Csf1r) and monocytic markers (Ccr2, Ly6c2) together. Embryonic macrophages interact closely with developing neural networks, while postnatal bone marrow-derived macrophages associate with blood vessels. Lack of fetal liver-derived macrophages disrupts nerve and vessel development and causes downregulation of genes related to neuronal diseases and protein digestion pathways. Our data suggest that fetal liver-derived macrophages, interacting with BATs developing sympathetic neural network, guide the development of tissue morphology. Understanding further the mechanism behind these events can unravel novel targets for BAT immunomodulation.

immunology↗

bioRxiv2024

Fast label-free live imaging reveals key roles of flow dynamics and CD44-HA interaction in cancer cell arrest on endothelial monolayers

Leukocyte extravasation is a key component of the innate immune response, while circulating tumor cell extravasation is a critical step in metastasis formation. Despite their importance, the mechanisms underlying leukocyte and tumor cell extravasation remain incompletely understood. Here, we developed an imaging pipeline that integrates fast, label-free live-cell imaging with deep learning-based image analysis to quantitatively track and compare the initial steps of extravasation--cell landing and arrest on an endothelial monolayer--under physiological flow conditions. We find that pancreatic ductal adenocarcinoma (PDAC) cells exhibit variable adhesion strength and flow sensitivity. Remarkably, some PDAC cells demonstrate comparable endothelial engagement as leukocytes, preferentially arresting at endothelial junctions, potentially due to increased stiffness at these sites, which leads to exposure to the underlying basal extracellular matrix. PDAC cells also tend to cluster in regions with high, heterogeneous expression of the endothelial CD44 receptor. Simulations suggest that clustering results from the combination of CD44-mediated attachment and localized flow disturbances that facilitate subsequent cell attachment. Targeting CD44 using siRNA or function-blocking antibodies, or degrading its ligand hyaluronic acid (HA), almost completely abolishes PDAC cell attachment. Overall, we demonstrate that cancer and immune cells share both common and unique features in endothelial adhesion under flow, and identify CD44 and HA as key mediators of PDAC cell arrest.

cell biology↗

bioRxiv2024

Early precursor-derived pituitary gland tissue-resident macrophages play a pivotal role in modulating hormonal balance

The pituitary gland is the central endocrine regulatory organ underneath the brain, producing and releasing a variety of hormones that coordinate major body functions. The physical location of the pituitary gland underneath the brain, though outside the protective blood-brain barrier, leads to a unique immune environment of the pituitary that has not been studied. Here, we defined the development, diversity, spatial niche, and origin of the pituitary gland macrophage subsets using single cell transcriptomics, fate mapping, and imaging. We identified early yolk sac precursors solely seeding pituitary gland macrophages which are maintained by proliferation. Macrophage depletion experiments unveiled the essential contribution of early macrophages in the pituitary glands hormonal production and in modulating the post-pubertal expression of genes related to the sexually dimorphic processes regulated by the pituitary gland. Altogether, these findings provide novel information on pituitary gland macrophages and advance our understanding of immune-endocrine system crosstalk.

immunology↗

bioRxiv2023

Single-cell transcriptome analysis of the early immune response in the lymph nodes of Borrelia burgdorferi-infected mice

Lyme borreliosis is a disease caused by Borrelia burgdorferi sensu lato bacteria. Borrelia burgdorferi is known to induce prolonged extrafollicular immune responses and abnormal germinal center formation. However, the mechanism behind this is poorly understood. The extrafollicular response is characterized by strong plasmablast induction and by an IgM, IgG3, and IgG2b dominant antibody production. These antibodies do not generate a neutralizing type of immunity, and the bacteria eventually establish a persistent infection. Here, we performed single-cell RNA sequencing to characterize the immune landscape of lymph node lymphocytes in the early Borrelia burgdorferi infection in a murine model. Our results indicate that four days after Borrelia burgdorferi infection, a notable B cell proliferation, immunoglobulin class switching to IgG3 and IgG2b isotypes, and plasma cell differentiation are induced, all of which are hallmarks of the extrafollicular immune response. In addition, we found infection-derived upregulation of suppressor of cytokine signalling genes Socs1 and Socs3, and downregulation of genes involved in MHC II antigen presentation in B cells. Our results support the central role of B cells in the immune response of a Borrelia burgdorferi infection, and provide cues of mechanisms behind the determination between extrafollicular and germinal center responses during Borrelia burgdorferi infection.

molecular biology↗

bioRxiv2022

Targeting a broad spectrum of KRAS-mutant cancers by hyperactivation-induced cell death

The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where numerous different activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds overactive mutant forms to limit oncogenic KRAS signalling and maintain RAS- activity at an optimal level. Depletion of SHANK3 results in hyperactivation of KRAS/mitogen-activated protein kinase (MAPK) signalling, which in turn selectively induces MAPK/ERK-dependent cell death in KRAS-mutant cancers. Furthermore, targeting of this therapeutic vulnerability through nanobody- or RNA interference- mediated disruption of the SHANK3-KRAS interaction reduces tumour growth in vivo. Thus, inhibition of the SHANK3-KRAS interaction represents a new pan-KRAS-mutant compatible strategy for selective killing of KRAS- mutant cancer cells through excessive signalling. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/508660v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@87e71forg.highwire.dtl.DTLVardef@56cf94org.highwire.dtl.DTLVardef@1561136org.highwire.dtl.DTLVardef@183f711_HPS_FORMAT_FIGEXP M_FIG C_FIG Schematic model of SHANK3-controlled cell fate in KRAS-mutant cancers. SHANK3 directly interacts with KRAS and competes with RAF for KRAS binding to sustain oncogenic RAS-MAPK/ERK signalling at an optimal level (i.e. below toxic oncogenic signalling) in KRAS-mutant cancers. SHANK3 silencing (1) and inhibition of SHANK3-KRAS interaction (2) drive KRAS-mutant cells into cell death.

cancer biology↗

bioRxiv2019

An expanded analysis framework for multivariate GWAS connects inflammatory biomarkers to functional variants and disease

Multivariate methods are known to increase the statistical power of association detection, but they have lacked essential follow-up analysis tools necessary for understanding the biology underlying these associations. We developed a novel computational workflow for multivariate GWAS follow-up analyses, including fine-mapping and identification of the subset of traits driving associations (driver traits). Many follow-up tools require univariate regression coefficients which are lacking from multivariate results. Our method overcomes this problem by using Canonical Correlation Analysis to turn each multivariate association into its optimal univariate Linear Combination Phenotype (LCP). This enables an LCP-GWAS, which in turn generates the statistics required for follow-up analyses. We implemented our method on 12 highly correlated inflammatory biomarkers in a Finnish population-based study. Altogether, we identified 11 associations, four of which (F5, ABO, C1orf140 and PDGFRB) were not detected by biomarker-specific analyses. Fine-mapping identified 19 signals within the 11 loci and driver trait analysis determined the traits contributing to the associations. A phenome-wide association study on the 19 putative causal variants from the signals in 176,899 individuals from the FinnGen study revealed 53 disease associations (p < 1x10-4). Several reported pQTLs in the 11 loci provided orthogonal evidence for the biologically relevant functions of the putative causal variants. Our novel multivariate analysis workflow provides a powerful addition to standard univariate GWAS analyses by enabling multivariate GWAS follow-up and thus promoting the advancement of powerful multivariate methods in genomics.

genetics↗

bioRxiv2019

Multivariate genome-wide association analysis of a cytokine network reveals variants with widespread immune, haematological and cardiometabolic pleiotropy

Cytokines are essential regulatory components of the immune system and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlie them, remain unknown. Here we aimed to identify and characterise genetic variants with pleiotropic effects on cytokines - to do this we performed a multivariate genome-wide association study on a correlation network of 11 circulating cytokines measured in 9,263 individuals. Meta-analysis identified a total of 8 loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. Bayesian colocalisation analysis revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins; on metabolic traits such as lipoprotein and lipid levels; on blood-cell related traits such as platelet count; and on disease traits such as coronary artery disease and type 2 diabetes.

genomics↗

bioRxiv2018

Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns

BackgroundInflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood.\n\nMethodsTo add understanding to the molecular mechanisms in inflammation, we performed a genome-wide association study (GWAS) on 16 circulating cytokines and cell adhesion molecules (inflammatory phenotypes) in Northern Finland Birth Cohort 1966 (NFBC1966, N=5,284). A subsequent meta-analysis was completed for 10 phenotypes available in a GWAS of three other Finnish population cohorts adding up to 13,577 individuals in the study. Complementary association tests were performed to study the effect of the ABO blood types on soluble adhesion molecule levels.\n\nResultsWe identified seven novel and confirmed six previously reported loci associating with at least one of the studied inflammatory phenotypes (p<3.1x10-9). We observed three loci associating with the concentration of soluble vascular cell adhesion molecule-1 (sVCAM-1), one of which is the ABO locus that has been previously associated with soluble E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) levels. Results from the complementary analyses suggest that the blood type B associates primarily with the concentration of sVCAM-1 while the A1 subtype shows a robust effect on sE-selectin and sICAM-1 levels. Furthermore, the genotypes in the ABO locus associating with higher soluble adhesion molecule levels tend to associate with lower low-density lipoprotein cholesterol level and lower cardiovascular disease risk.\n\nConclusionThe present results extend the knowledge about genetic factors contributing to the inflammatory load. Our findings suggest that two distinct mechanisms contribute to the soluble adhesion molecule levels at the ABO locus. The negative correlation between the genetic effects on soluble adhesion molecule levels and cardiovascular traits in this locus further suggests that increased soluble adhesion molecule levels per se may not be a risk factor for cardiovascular disease.

genetics↗