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Metabolic and Proteomic Signatures Differentiate Inflammatory Phenotypes from Cancer and Predict Treatment Response in Patient Sera
Get PDFTumors shift their metabolic needs to enable uncontrolled proliferation. Therefore, metabolic assessment of cancer patient sera provides a significant opportunity to noninvasively monitor disease progression and enable mechanistic understanding of the pathways that lead to response. Here, we show Raman spectroscopy (RS), a highly sensitive and label-free analytical tool, is effective in metabolic profiling across diverse cancer types in patient sera from both pancreatic ductal adenocarcinoma (PDAC) and locally advanced rectal cancer (LARC). We also combine metabolic data with proteomic signatures to predict treatment response. Our data show RS peaks successfully differentiate PDAC patients from healthy controls. Peaks associated with sugars, tyrosine, and DNA/RNA distinguish PDAC patients from chronic pancreatitis, an inflammatory condition that is notoriously difficult to discern from PDAC via current clinical approaches. Furthermore, our study is expanded to investigate response to chemoradiation therapy in LARC patient sera where at pre-treatment multiple metabolites including glycine, carotenoids, and sugars are jointly correlated to the neoadjuvant rectal (NAR) score indicative of poor prognosis. Via classical univariate AUC–ROC analysis, several RS peaks were found to have an AUC\u3e0.7, highlighting the potential of RS in identifying key metabolites for differentiating complete and poor responders of treatment. Gene set enrichment analysis revealed enrichment of metabolic, immune, and DDR-related pathways associated with CRT response. Notably, RS-derived metabolites were significantly correlated with multiple immune signaling proteins and DDR markers, suggesting these distinct analytes converge to reflect systemic changes within the tumor microenvironment. By integrating metabolic, proteomic, and DDR data, we identified pre-treatment activation of galactose and glycerolipid metabolism, and post-treatment engagement of cell cycle and p53 signaling pathways. Our findings show that RS, when integrated with complementary protein marker analysis, holds the potential to bridge the translational divide enabling a clinically relevant approach for both diagnosis and predicting response in patient samples
Claudin-1-Mediated Signaling and Therapy Resistance in Colorectal Cancer: From Mechanism to Translation
Get PDFColorectal cancer (CRC) remains a leading cause of cancer-related mortality, with metastatic cases showing poor response to chemotherapy due to both intrinsic and acquired therapy resistance. Claudin-1 (CLDN1), a tight junction protein, is overexpressed and mislocalized outside of tight junctions in CRC, where it contributes to an aggressive, metastatic phenotype. Although this causal relationship has been well established, the mechanisms by which CLDN1 promotes tumor progression were unclear due to its lack of intrinsic enzymatic activity. This dissertation investigates the molecular mechanisms through which CLDN1 drives oncogenic signaling, its role in therapy resistance, and its translational potential as both a biomarker and therapeutic target in CRC.
Single-cell analysis of CRC patient tumors shows that CLDN1 is selectively overexpressed in stem-like tumor cells, with minimal expression in normal colon tissue. We demonstrate that CLDN1 directly interacts with Ephrin receptor A2 (EPHA2) via its C-terminal PDZ-binding motif, stabilizing EPHA2 by preventing its lysosomal degradation. This interaction activates non-canonical EPHA2 signaling through the AKT/mTOR pathway, enhancing stemness and chemoresistance.
We further characterized the broader CLDN1 interactome and its associated gene expression programs in CRC. Notably, CLDN1 engages with multiple signaling molecules and drives transcriptional changes that confer resistance to oxaliplatin-based therapies, but not irinotecan. This selective resistance was confirmed in both mouse models and ex vivo patient-derived organoids, supporting the potential of CLDN1 as a predictive biomarker for guiding first-line treatment selection.
To explore therapeutic applications, we evaluated the efficacy of a humanized monoclonal antibody (H3L3) targeting non-junctional CLDN1. H3L3 treatment inhibited AKT/mTOR signaling and significantly reduced tumor growth in xenograft and patient-derived organoid models.
Lastly, we developed a near-infrared fluorophore-conjugated anti-CLDN1 antibody for in vivo imaging. This probe selectively labeled CLDN1-expressing CRCs, including distant metastases, in both xenograft and orthotopic models, demonstrating its potential utility for tumor detection and fluorescence-guided surgery.
Together, these findings identify CLDN1 as a critical mediator of CRC progression and chemoresistance, with significant translational potential as a biomarker, therapeutic target, and imaging agent for CRC diagnosis and treatment
A Novel Multi-Disciplinary Opioid Tapering Program for Standardized Post-Operative Opioid Use
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A Quality Improvement Initiative: Retrospective Analysis of Impact of Cytogenetics in Orthopedic Oncologic Diagnosis and Subsequent Management
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Outcomes of Acute Myocardial Infarction in Patients With vs. Without Systemic Lupus Erythematosus
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Investigating the Efficacy and Safety of a Dose-Dense Paclitaxel, Cyclophosphamide With Trastuzumab in Stage Ⅰ-Ⅱ Human Epidermal Growth Factor Receptor 2 (HER2) Positive Breast Cancer
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Pain From Cervical Radiculopathy Effectively Treated With Ultrasound-Guided Erector Spinae Plane Block In a Complex Patient
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The Splicing Factor PTBP1 Interacts with RUNX1 and is Required for Leukemia Cell Survival
No full textAcute myeloid leukemia (AML) is a neoplastic disease characterized by the uncontrolled proliferation and accumulation of immature and non-functional myeloid blast cells. One of the most frequently mutated transcription factors implicated in the pathogenesis of AML is Runt-related Transcription Factor 1 (RUNX1). RUNX1 is essential for definitive hematopoiesis and is a key hematopoietic regulator with well-known roles in leukemia. Previous work from our lab demonstrated that Histone Deacetylase 1 (HDAC1), a known RUNX1 partner, is unexpectedly required for active transcription of RUNX1 target genes in Acute Myeloid Leukemia (AML). This implies a non-histone role for HDAC1 in regulating components of the RUNX1 complex.
To decipher the role of HDAC1 in recruiting proteins to the RUNX1 complex, we immunoprecipitated RUNX1 in the presence of a HDAC1 inhibitor, entinostat, and performed mass spectrometry. We discovered that Polypyrimidine Tract Binding Protein 1 (PTBP1), a splicing regulator, interacts with RUNX1 in an HDAC1-dependent manner, where the interaction is significantly reduced in the presence of entinostat. This association was observed in a variety of leukemia subtypes as well as healthy hematopoietic stem cells. Chromatin profiling revealed extensive genome-wide overlap in sites occupied by RUNX1 and PTBP1, with significant enrichment at promoters of actively transcribed genes, specifically those involved in metabolism. Loss of PTBP1 in AML cells led to widespread alterations in RNA splicing and decreased expression of genes whose 3 promoters are bound by both factors, including metabolic genes. In agreement with these findings, we found that loss of PTBP1 reduced glycolytic output and glucose uptake, increased DNA damage, and ultimately caused leukemia cell death. Moreover, we showed that loss of PTBP1 sensitized leukemia cells to the chemotherapeutic agent, cytarabine. Finally, using entinostat to disrupt this interaction, we observed downregulation of metabolic proteins. Based on our data, we propose that the interaction between RUNX1 and PTBP1 facilitates expression of metabolic proteins essential for leukemia cell growth and survival