Biology subjects

Haglund, C.

Publications and source records attributed to Haglund, C..

10 recordsLinked to original sources

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

Colorectal cancer heterogeneity co-evolves with tumor architecture to determine disease outcome

Intratumoral heterogeneity, originating from genetic, epigenetic, and phenotypic cellular diversity, is pervasive in cancer. As these heterogeneous states employ diverse mechanisms to promote tumor progression, metastasis, and therapy resistance, emergence of cancer heterogeneity is one of the most significant barriers to curative treatment. Here we leverage deep learning approaches to develop a high-throughput image-analysis paradigm with subcellular resolution that quantifies and predicts colorectal cancer (CRC) patient outcome based on tissue architecture and nuclear morphology. We further combine this approach with spatial transcriptomics, multiplex immunohistochemistry, and patient-derived organoids to uncover a dynamic, co-evolutionary relationship between tumor architecture and cell states. We identify clinically relevant architectural interfaces in CRC tissue that diversify cellular identities by favoring distinct cancer stem cell states and thus promote evolution of tumor heterogeneity. Specifically, tissue fragmentation and associated compressive forces promote loss of classic stem cell signature and acquisition of fetal/regenerative stem cell states, which initially emerges as a hybrid state with features of epithelial-to-mesenchyme (EMT) transition. Additional tumor stroma communication then diversifies these states into distinct stem cell and EMT states at the invasive margins of tumors. Reciprocally, Wnt signaling state of tumor cells tunes their responsiveness to tissue architecture. Collectively, this work uncovers a feedback loop between cell states and tissue architecture that drives cancer heterogeneity and cell state diversification. Machine learning-based analyses harness this co-dependency, independently of mutational status or cancer stage, to predict patient outcome.

cancer biology↗

bioRxiv2025

High-resolution integrative analysis allows characterization and spatial annotation of normal and cancer-associated colon fibroblasts

Fibroblasts represent key regulators of colon homeostasis, and cancer-associated fibroblasts (CAFs) play pivotal roles in colorectal cancer (CRC). Despite their critical influence, a consensus view of adult human colon fibroblast and CRC CAF heterogeneity, spatial organization, and developmental trajectories is currently lacking. Here, we address this gap by performing a comprehensive characterization of colonic fibroblasts and CRC CAFs. Using large-scale integration of single-cell RNA-sequencing datasets from normal colon and CRC we mapped the fibroblast subpopulations. Spatial transcriptomics, immunohistochemistry, and in situ hybridization were used for validation and computational analyses to predict developmental trajectories and transcription factors underlying CAF activation. Subepithelial myofibroblasts (SEMFs), mucosa-associated fibroblasts (MAFs), and submucosa-associated fibroblasts (SAFs) were identified as the main colon fibroblast subtypes, and in mice, further divided into location-based subclusters. We also identified a novel colon fibroblast subset: muscle-embedded interstitial fibroblasts (MIFs). CRCs contained normal fibroblasts as well as four cancer-specific CAF populations: inflammatory CAFs (iCAFs), matrix CAFs (mCAFs), and two precursor CAF (preCAF) subtypes. Our data suggested that iCAFs originate from SEMFs through a preCAF1 intermediate phenotype, while mCAFs derive from SAFs/MIFs via preCAF2s. Transcription factors PRRX1, MAFB, and TWIST1 were uncovered as potential regulators of CAF identity and CTHRC1 was identified as a specific and sensitive pan-CAF marker in CRC. Our study presents a detailed framework for understanding colon fibroblast and CRC CAF heterogeneity. This work lays the groundwork for future research into the roles and potential therapeutic relevance of different CRC CAF subsets.

cancer biology↗

bioRxiv2024

HOXB6 and HOXB8 control immune-cancer cell interactions in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer lacking effective drugs and therefore new treatment targets are needed. Transcriptomic analysis comparing human embryonic and PDAC tissue identified a large overlap of expression profiles suggesting a re-initiation of developmental programs in pancreatic cancer. Specifically, we identified the transcription factors HOXB6 and HOXB8 as potential key regulators in PDAC. Loss of HOXB6 and HOXB8 in pancreatic cancer cells inhibited cell proliferation, induced apoptosis and senescence and enhanced gemcitabine sensitivity. Moreover, reduced HOXB6 and HOXB8 expression in pancreatic and lung adenocarcinoma cell lines affected transcription of immune response pathways which resulted in an increased sensitivity of cancer cells to anti-tumorigenic activities of macrophages suggesting that the HOXB6 and HOXB8 immune regulatory pattern is conserved in different cancer types. Additionally, naive M0 macrophages exposed to HOXB8 deficient PDAC cells were unable to differentiate into tumor associated macrophages, suggesting that HOXB8 promotes the transition of initial anti-tumor macrophage to a tumor-promoting macrophage phenotype in pancreatic cancer. Our findings indicate that HOXB6 and HOXB8 play important roles in regulating cell proliferation, immune response and treatment resistance to promote pancreatic cancer tumorigenesis and could be useful therapeutic targets.

cancer biology↗

bioRxiv2023

Solid tumor growth depends on an intricate equilibrium of malignant cell states

Control of cell identity and number is central to tissue function, yet principles governing organization of malignant cells in tumor tissues remain poorly understood. Using mathematical modeling and candidate-based analysis, we discover primary and metastatic pancreatic ductal adenocarcinoma (PDAC) organize in a stereotypic pattern whereby PDAC cells responding to WNT signals (WNT-R) neighbor WNT-secreting cancer cells (WNT-S). Leveraging lineage-tracing, we reveal the WNT-R state is transient and gives rise to the WNT-S state that is highly stable and committed to organizing malignant tissue. We further show that a subset of WNT-S cells expressing the Notch ligand DLL1 form a functional niche for WNT-R cells. Genetic inactivation of WNT secretion or Notch pathway components, or cytoablation of the WNT-S state disrupts PDAC tissue organization, suppressing tumor growth and metastasis. This work indicates PDAC growth depends on an intricately controlled equilibrium of functionally distinct cancer cell states, uncovering a fundamental principle governing solid tumor growth and revealing new opportunities for therapeutic intervention.

cancer biology↗

bioRxiv2023

E2F transcription factors promote tumorigenicity in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs. Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we identified embryonic signalling pathways that were reinitiated during tumor formation and expansion. Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells. In conclusion, our findings show that E2F1 and E2F8 transcription factors regulate cell proliferation, survival, and migration during pancreatic carcinogenesis.

cancer biology↗

bioRxiv2022

Efficacy and safety of glycosphingolipid SSEA-4 targeting CAR-T cells in solid tumors

Chimeric antigen receptor (CAR) T-cell immunotherapies for solid tumors face critical challenges such as heterogeneous antigen expression. We characterized SSEA-4 cell-surface glycolipid as a target for CAR-T cell therapy. SSEA-4 is mainly expressed during embryogenesis but is also found in several cancer types making it an attractive tumor-associated antigen. Anti-SSEA-4 CAR-T cells were generated and assessed pre-clinically in vitro and in vivo for anti-tumor response and safety. SSEA-4 CAR-T cells effectively eliminated SSEA-4 positive cells in all tested cancer cell lines whereas SSEA-4 negative cells lines were not targeted. In vivo efficacy and safety studies using NSG mice and the high-grade serous ovarian cancer cell line OVCAR4 demonstrated a remarkable and specific anti-tumor response at all CAR-T cell doses used. At high T cell doses, CAR-T cell-treated mice showed signs of health deterioration after a follow-up period. However, severity of toxicity was reduced with delayed onset when lower CAR-T cell doses were used. Our data demonstrate the efficacy of anti-SSEA-4 CAR-T therapy; however, safety strategies, such as dose-limiting and/or equipping CAR-T cells with combinatorial antigen recognition should be implemented for its potential clinical translation.

cancer biology↗

bioRxiv2020

PROX1 transcription factor is a master regulator of myogenic and oncogenic features of rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue cancer in need for novel therapies. Here we show that the PROX1 transcription factor, which is essential for normal myoblast differentiation, is highly expressed in RMS tumors. We demonstrate that PROX1 is needed for RMS cell stemness and growth in vitro, and for RMS tumor formation in mouse xenograft models. In addition, we unveil that PROX1 is an essential for myogenic properties in RMS. PROX1 depletion reprogrammed the RMS transcriptome to resemble benign mesenchymal stem cells and repressed many of the previously identified RMS effector transcripts and myogenic genes. By using proximity labeling and mass spectrometry, we found that PROX1 interacts with the NuRD and CoREST complexes containing class I HDACs. Our studies reveal a major role of PROX1-HDAC interaction in RMS and give insights that inhibiting this interaction could be a promising therapeutic approach.

cancer biology↗

bioRxiv2019

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Kaposi sarcoma (KS) is a tumour of endothelial origin caused by KS herpesvirus (KSHV) infection and suggested to originate from lymphatic endothelial cells (LECs). While KSHV establishes latency in virtually all susceptible cell types, LECs support a spontaneous lytic gene expression program with high viral genome copies and release of infectious virus. Here, we investigated the role of PROX1, SOX18 and COUPTF2, drivers of lymphatic endothelial fate during embryogenesis, in this unique KSHV infection program. We found that these factors were co-expressed in KS tumours with the viral lytic marker K8.1, and that SOX18 and PROX1 regulate KSHV infection via two independent mechanisms. SOX18 binds to the viral origins of replication and its depletion or chemical inhibition significantly reduced the KSHV genome copies in LECs. PROX1 interacts with ORF50, the initiator of the lytic cascade, increases lytic gene expression and virus production and its depletion reduces KSHV spontaneous lytic reactivation. Upon lytic replication, PROX1 binds to the KSHV genome in the promoter region of ORF50 and enhances its transactivation activity. These results demonstrate the importance of two endothelial transcription factors in the regulation of the KSHV life cycle and introduce SOX18 inhibition as a potential, novel therapeutic modality for KS.

microbiology↗