Biology subjects

Pantel, K.

Publications and source records attributed to Pantel, K..

10 recordsLinked to original sources

bioRxiv2026

Comprehensive ctDNA Profiling Enables Tissue-of-Origin Prediction and Actionable Biomarker Detection in Cancer of Unknown Primary

Most patients with cancer of unknown primary (CUP) still receive platinum-based chemotherapy and have a poor prognosis, with overall survival of less than one year. Recent studies suggest improved outcomes with molecularly guided or site-specific therapies informed by molecular tissue profiling. Here, we analyzed ctDNA from 190 CUP patients using an integrated genomic and epigenomic assay to identify actionable alterations and predict tissue-of-origin (ToO). Integration of actionable biomarkers, ToO prediction and clinical data yielded diagnostic, prognostic or therapeutic information in 90% of unfavorable CUP cases and 88% of patients analyzed at first diagnosis. High ctDNA tumor fraction was associated with poorer prognosis in both favorable and unfavorable CUP. These findings highlight the clinical utility of ctDNA analysis for therapeutic decision-making in CUP and support its incorporation into the diagnostic work-up, particularly when tissue samples are unavailable or insufficient for molecular testing.

Cancer Biology↗

bioRxiv2026

Learning from Drops: AI-Guided Integration of Liquid Biopsy Features in Cancer Studies

Cancer is a major global health issue with rising incidence and mortality. Early detection, tumor characterization, and disease surveillance are crucial for timely and effective treatment, ultimately reducing mortality rates. Liquid biopsy (LB) has emerged as a valuable detection tool offering a non-invasive method to determine tumor-derived biomarkers in body fluids with demonstrated translational potential. To increase biomarker sensitivity, high-throughput sequencing platforms deliver massive volumes of data. Artificial Intelligence (AI) is pivotal in enabling huge and complex data integration. This contribution aims to assess the current state of integrative AI-based research in the LB field and provide methodological guidance. First, we conducted a PubMed search and found that the literature is sparse in studies integrating LB features, particularly by applying AI. When adopting the latter approach, defining the study objectives is crucial to guide the subsequent methodological aspects, including study design, patient selection criteria, sample size, nature of the LB features, and metadata to collect. Specifically, we propose strategies and tools for data preprocessing, including normalization and batch correction, as well as handling outliers and missing data. Furthermore, we recommend various Machine/Deep Learning approaches for feature selection techniques to ensure model robustness, and we highlight the importance of undergoing rigorous internal and external validations of the selected models. Assessing clinical utility and interpretability is often overlooked but fundamental for real-world implementation. In conclusion, we provide the LB scientific community with an AI-based methodological guidance to bridge the two fields and enhance the integrative analysis of LB features. Graphical abstractWorkchart for multiomics integrative studies in the liquid biopsy field. Note: CTCs, circulating tumor cells; ctDNA, circulating tumor-DNA; TEPs, tumor-educated platelets; miRNA, microRNA; cfRNAs, cell-free RNAs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/724535v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1f250b2org.highwire.dtl.DTLVardef@18fe36corg.highwire.dtl.DTLVardef@19c02b9org.highwire.dtl.DTLVardef@176f6e0_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Red blood cell-tumour cell interactions promote tumour cell progression

One critical step in the metastatic cascade is the survival of circulating tumour cells (CTCs) within the bloodstream. While numerous interactions between CTCs and various hematopoietic cells have been described, the role of red blood cells (RBCs) in this process remains underexplored. This study investigates the interactions between tumour cells and RBCs from breast and lung cancer patients, revealing significant phenotypic and functional changes in the tumour cells, unlike when the contact is with RBCs from healthy donors. In vitro co-culture of cancer cell lines with RBCs from metastatic cancer patients resulted in increased tumour cell attachment accompanied by morphological changes. Additionally, RBCs-primed tumour cells showed increased adhesion and disruption of the endothelial barrier in vitro and increased invasiveness both in vitro and in vivo. Transcriptomic analysis showed that RBCs from metastatic breast cancer patients induce significant gene expression changes, notably upregulating PAK4, which enhances migration and epithelial-mesenchymal transition. PAK4 inhibition reduced these effects. Proteomic studies revealed substantial remodelling, including actin-related changes and the accumulation of VASP at cell edges, promoting directional migration. Clinically, higher RBC distribution width (RDW) in metastatic breast cancer patients is associated with increased CTC counts and worse outcome. This study highlights the previously unrecognized role of RBCs in promoting metastatic behaviours in cancer cells and suggests potential therapeutic targets, such as PAK4, to counteract these effects. Further exploration of RBCs-tumour cell interactions could provide new insights into metastatic mechanisms and improve cancer prognosis and treatment strategies. Key PointsO_LIThis study reveals the previously unknown role of RBCs in enhancing tumour cell invasiveness and metastatic potential. C_LIO_LITumour cells undergo significant phenotypic and functional changes after contact with RBCs from cancer patients. C_LI

cancer biology↗

bioRxiv2024

NSCLC patients with oligo-metastatic brain disease show an altered CD4 T-cells immune profile

BackgroundLung cancer is the leading cause of cancer-related deaths worldwide, with brain metastasis (BM) occurring in 40% of advanced non-small cell lung cancer (NSCLC) patients. In 15% of these patients, the brain is the only affected organ (oligo-metastasis), corresponding to improved prognosis compared to widespread disease. Thus far, it is unknown if the metastatic dissemination to the brain without systemic metastases is a consequence of the immune systems ability to control systemic tumor outgrowth. MethodsHere, we investigated the local and peripheral immune cell composition in NSCLC BM patients, and identified new immune patterns related to the occurrence of brain metastases either as oligo- or poly-metastatic disease. ResultsThe multi-parametric immune phenotyping of peripheral blood revealed a downregulation of KLRG1 in CD8+ T-cells and an increase in CD4+ TH17 cells and elevated IL-17 levels in the blood of all NSCLC BM patients compared to healthy individuals. In addition, BM patients CD4+ T cells showed less CD73 expression with reduced effector memory differentiation. Furthermore, we observed less intra-tumoral infiltration in tumor tissues and a distinctive CD4+ T-cell profile in oligo-synchronous BM, both in the tumor microenvironment and peripheral blood compared to poly-metastatic BM patients. Moreover, 5'-ectonucleotidase CD73 was significantly upregulated in CD4 and T-regulatory cells of oligo-synchronous BM. ConclusionsThese results indicate that oligo-synchronous BM exhibits a more pronounced alteration in the CD4 T-cell immune profile both locally at the tumor site and systemically. Key PointsO_LIBM patients exhibit a skewed systemic immune profile, characterized by downregulation of KLRG1 in CD8+ and induction of TH17/IL-17 axis and CD73 in CD4+ T-cells. C_LIO_LIOligo-synchronous BM displayed a distinct CD4+ T-cell profile in both TME and peripheral blood. C_LI Importance of the StudyThis study presents a novel insight into immune profiles of brain metastasis types in NSCLC patients. Examining tissues and PBMCs sheds light on the disease and uncovers unique immune responses within distinct brain metastasis patterns. This research offers valuable knowledge for improved understanding and identifying potential prognosis markers.

cancer biology↗

bioRxiv2024

TAM receptors control actomyosin dynamics in osteoclasts via RHOA-COFILIN-MYOSIN II signaling

The TAM family of receptor tyrosine kinases were recently identified to regulate bone homeostasis by controlling osteoblasts and bone formation. Despite extensive knowledge of TAM receptor function in the mononuclear phagocyte system, the role of TAM receptors in osteoclasts remains largely unknown. Here, we identify a physiological regulatory system including MERTK and TYRO3 in osteoclasts controlling RHOA-ROCK-COFILIN/Myosin II signaling, thereby antagonistically regulating osteoclast-mediated bone remodeling to maintain bone homeostasis. Myeloid-specific lysozyme M-mediated deletion of Mertk led to increased bone mass in mice. In early stages of RANKL-induced osteoclast differentiation MERTK promotes amoeboid migration mode in osteoclast precursor cells by inducing RHOA-COFILIN-MLC2 pathway leading to increased osteoclast formation. In contrast, TYRO3 inhibits RHOA-ROCK signaling in osteoclast precursor cells thereby inhibiting these processes. Furthermore, we unraveled an inhibitory role of MERTK as well as TYRO3 in osteoclast differentiation and function. In line with this, mice with cathepsin K-mediated deletion of Mertk and Tyro3 exhibited an osteoporotic bone phenotype. We found that osteoclast precursor cell morphology dictates its fusion capacity and identified MERTK as a negative regulator of osteoclast fusion. In multinucleated cells, deletion of Mertk inhibits actin ring formation by mediating central actomyosin contraction and inactivation of COFILIN. In contrast, spatially well-ordered RHOA activation at adhesion structures, induced by loss of Tyro3, improves osteoclast biomechanotransduction to ameliorate podosome belt formation and enhance osteoclast function. By using a syngeneic breast cancer bone metastasis osteolysis models we identified TYRO3 as a bone protective receptor for osteolytic bone diseases, whereas MERTK represents a pharmacologic accessible target to inhibit osteoclast formation because its stimulatory effects of osteoclast precursors prevail the inhibitory effects on mature osteoclasts. Next to the recently uncovered role of MERTK as a target for osteoanabolic therapy MERTK may represent a one-drug two-target treatment strategy to increase osteoblast function and reduce osteoclast formation for treatments of bone diseases.

cell biology↗

bioRxiv2023

Corepressor inactivation through tandem linear motif-induced polymerization

While the elucidation of regulatory mechanisms of folded proteins is facilitated due to their amenability to high-resolution structural characterization, investigation of these mechanisms in disordered proteins is more challenging due to their structural heterogeneity, which can be captured by a variety of biophysical approaches. Here, we used the transcriptional master corepressor CtBP, which binds the putative metastasis suppressor RAI2 through repetitive SLiMs, as a model system. Using cryo-electron microscopy embedded in an integrative structural biology approach, we show that RAI2 unexpectedly induces CtBP polymerization through filaments of stacked tetrameric CtBP layers. These filaments lead to RAI2-mediated CtBP nuclear foci and relieve its corepressor function in RAI2-expressing cancer cells. The impact of RAI2-mediated CtBP loss-of-function is illustrated by the analysis of a diverse cohort of prostate cancer patients, which reveals a substantial decrease in RAI2 in advanced treatment-resistant cancer subtypes. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions. The specific properties of these repeated interactions open up new therapeutic opportunities.

molecular biology↗

bioRxiv2020

RNF40-dependent epigenetic regulation of actin cytoskeletal dynamics is required for HER2-driven mammary tumorigenesis

The HER2-driven breast cancer subtype displays a particularly aggressive behavior. Alterations of the epigenome are common in cancers and represent attractive novel molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by its obligate heterodimeric E3 ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specific Rnf40 deletion and identified an unexpected tumor-supportive role of RNF40 in HER2-positive breast cancer. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2-positive breast cancer, revealing the RNF20/RNF40/H2Bub1 axis as a possible tumor context-dependent therapeutic target in breast cancer. Statement of significanceHER2-positive breast cancer patients frequently develop resistance to anti-HER2 therapies. Here we demonstrate that RNF20/RNF40-mediated H2B monoubiquitination supports the oncogenic properties of cancer cells of this subtype by regulating actin dynamics. The RNF20/RNF40/H2Bub1 axis may therefore represent an attractive drug target for novel therapies.

cancer biology↗

bioRxiv2018

ALDH1-positive intratumoral stromal cells indicate epithelial differentiation and good prognosis in prostate cancer

Aldehyde dehydrogenase 1 (ALDH1) characterizes tumor-initiating cells in solid tumors, however little is known about its expression in intratumoral stromal cells. Herein, we aimed to dissect its potential dual relevance in prostate cancer (PCa).\n\nALDH1 expression was evaluated immunohistochemically in tumor and stromal cells in primary PCa and metastasis. It was correlated with clinico-pathological parameters, outcome of patients, and selected protein expression (CK5/6, CK14, CK8/18, CK19, EpCAM, Ki-67, E-cadherin, N-cadherin, and vimentin).\n\nALDH1 protein was detected in tumor and stromal cells in 16% and 67% of 348 primary PCa, respectively. Tumor cell ALDH1 expression was associated with advanced tumor (T) status (p=0.009), higher Gleason score (p=0.016), shorter time to biochemical recurrence (BR) (p=0.010) and CK14 expression (p=0.023). Stromal cell ALDH1 expression correlated with lower T status (p=0.008), N0 status (p=0.017), lower Gleason score (p=0.016) and longer time to BR (p=0.017). In the subgroup of dAmico high-risk patients it occurred even to be an independent predictor of good prognosis (multivariate analysis, p=0.050). ALDH1 was found in stroma of tumors characterized by CK8/18 (p=0.033) or EpCAM expression (p<0.001) and rarely by epithelial-mesenchymal transition defined as CK8/18(-)vimentin(+) phenotype (p=0.003). ALDH1 was detected in tumor cells and stroma of 33% and 41% of hormone naive lymph node metastases (n=63), 52% and 24% of castration resistant bone metastases, as well as 89% and 28% of castration resistant visceral metastases (n=21), respectively.\n\nWe have determined that contrary to tumor cell ALDH1, the presence of stromal ALDH1 is associated with a more differentiated tumor epithelial phenotype in primary PCa, improved clinical outcome, and is less frequent in PCa metastases.\n\nAbbreviations

cancer biology↗

bioRxiv2018

Somatic aberrations of BRCA1 gene are associated with progressive and stem cell-like phenotype of prostate cancer

BackgroundBRCA1 is a pivotal tumor suppressor. Its dysfunction is known to play a role in different tumor entities. Among others, BRCA1 germline mutations account for higher risk and more aggressive course of prostate cancer (PCa). In addition, somatic BRCA1 gene loss was demonstrated to be a signature of PCa dissemination to regional lymph nodes and peripheral blood, and indicate worse clinical outcome. In order to substantiate the data for BRCA1 gene loss in PCa and to reveal its phenotypical background, BRCA1 gene status was assessed in a large cohort of PCa patients and compared to different molecular factors.\n\nMethodsBRCA1 gene dosage was assessed in 2398 tumor samples from 1199 PCa patients using fluorescent in situ hybridization. It was compared to clinic-pathological parameters, patients outcome as well as selected proteins (Ki-67, apoptosis marker, cytokeratins, vimentin, E- and N-cadherin, ALDH1 and EGFR) examined by immunohistcohemistry.\n\nResultsBRCA1 losses were found in 10%, whereas gains appeared in 7% of 603 informative PCa patients. BRCA1 losses correlated to higher T status (p=0.027), Gleason score (p=0.039), shorter time to biochemical recurrence in patients with Gleason score >7 independently of other factors (multivariate analysis, p=0.005) as well as expression of proteins regulating stemness and epithelial-mesenchymal transition i.e. ALDH1 (p=0.021) and EGFR (p=0.011), respectively. BRCA1 gains correlated to shorter time to metastasis (p=0.012) and expression of ALDH1 (p=0.014).\n\nConclusionsThe presented results support the assumption that BRCA1 gene losses contribute to a progressive and stem cell-like phenotype of PCa. Furthermore, they reveal that also BRCA1 gain might mark more invasive tumors.

cancer biology↗

bioRxiv2017

Hemodynamic forces tune the arrest, adhesion and extravasation of circulating tumor cells

Metastatic seeding is driven by cell-intrinsic and environmental cues, yet the contribution of biomechanics is poorly known. We aim to elucidate the impact of blood flow on the arrest and the extravasation of circulating tumor cells (CTCs) in vivo. Using the zebrafish embryo, we show that arrest of CTCs occurs in vessels with favorable flow profiles where flow forces control the adhesion efficacy of CTCs to the endothelium. We biophysically identified the threshold values of flow and adhesion forces allowing successful arrest of CTCs. In addition, flow forces fine-tune tumor cell extravasation by impairing the remodeling properties of the endothelium. Importantly, we also observe endothelial remodeling at arrest sites of CTCs in mouse brain capillaries. Finally, we observed that human supratentorial brain metastases preferably develop in areas with low perfusion. Altogether, these results demonstrate that hemodynamic profiles at metastatic sites regulate key steps of extravasation preceding metastatic outgrowth.

cancer biology↗