bims-tumhet 2024-07-14 papers

Issue of 2024–07–14
eight papers selected by
Sergio Marchini, Humanitas Research

Cancer Res Commun. 2024 Jul 12.

Spatial landscape of malignant pleural and peritoneal mesothelioma tumor immune microenvironment.

Xiaojun Ma, David Lembersky, Elena S Kim, Michael J Becich, Joseph R Testa, Tullia C Bruno, Hatice U Osmanbeyoglu.

Immunotherapies have demonstrated limited clinical efficacy in malignant mesothelioma treatment. We conducted multiplex immunofluorescence (mIF) analyses on tissue microarrays (n=3) from malignant peritoneal (MPeM, n=25) and pleural (MPM, n=88) mesothelioma patients. Our study aimed to elucidate spatial distributions of key immune cell populations and their association with LAG3, BAP1, NF2, and MTAP, with MTAP serving as a CDKN2A/B surrogate marker. Additionally, we examined the relationship between the spatial distribution of major immune cell types with MM patient prognosis and clinical characteristics. We observed a higher degree of interaction between immune cells and tumor cells in MPM compared to MPeM. Notably, within MPM tumors, we detected a significantly increased interaction between tumor cells and CD8+ T cells in tumors with low BAP1 expression compared to those with high BAP1 expression. To support the broader research community, we have developed The Human Spatial Atlas of Malignant Mesothelioma (https://mesotheliomaspatialatlas.streamlit.app/), containing mIF and hematoxylin and eosin (H&E) images.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0524

Clin Cancer Res. 2024 Jul 08.

Novel Therapies in Cancer: Trials and Tribulations.

Saiama N Waqar, Ramaswamy Govindan.

Clinical trials are the backbone for advancing therapeutic options for patients diagnosed with cancer. Yet only 7.1% of patients with cancer participate in clinical trials in the United States. We review some of the reasons for poor accrual and discuss potential solutions.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-1127

Nat Rev Clin Oncol. 2024 Jul 11.

Targeting chromosomal instability in patients with cancer.

Duaa H Al-Rawi, Emanuele Lettera, Jun Li, Melody DiBona, Samuel F Bakhoum.

Chromosomal instability (CIN) is a hallmark of cancer and a driver of metastatic dissemination, therapeutic resistance, and immune evasion. CIN is present in 60-80% of human cancers and poses a formidable therapeutic challenge as evidenced by the lack of clinically approved drugs that directly target CIN. This limitation in part reflects a lack of well-defined druggable targets as well as a dearth of tractable biomarkers enabling direct assessment and quantification of CIN in patients with cancer. Over the past decade, however, our understanding of the cellular mechanisms and consequences of CIN has greatly expanded, revealing novel therapeutic strategies for the treatment of chromosomally unstable tumours as well as new methods of assessing the dynamic nature of chromosome segregation errors that define CIN. In this Review, we describe advances that have shaped our understanding of CIN from a translational perspective, highlighting both challenges and opportunities in the development of therapeutic interventions for patients with chromosomally unstable cancers.

DOI: https://doi.org/10.1038/s41571-024-00923-w

Clin Cancer Res. 2024 Jul 08.

Tumor Mutational Load: A Novel Predictor for Clinical Benefit of Pembrolizumab.

Fang-Chi Hsu, Yun Yen.

A recent study evaluated the efficacy of pembrolizumab across various cancers, classified according to tumor mutational load (TML) defined by whole-genome sequencing. Tumors exhibiting intermediate to high TML showed improved clinical benefit from pembrolizumab. This proof-of-concept study highlights clinical value of TML in patient selection, advancing precision immunotherapy and treatment strategies.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-1261

Nat Commun. 2024 Jul 09. 15(1): 5763

Circulating KRAS G12D but not G12V is associated with survival in metastatic pancreatic ductal adenocarcinoma.

While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy ("PRINCE", NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.

DOI: https://doi.org/10.1038/s41467-024-49915-5

Arch Toxicol. 2024 Jul 12.

A multi-biomarker micronucleus assay using imaging flow cytometry.

Danielle S G Harte, Anthony M Lynch, Jatin Verma, Paul Rees, Andrew Filby, John W Wills, George E Johnson.

Genetic toxicity testing assesses the potential of compounds to cause DNA damage. There are many genetic toxicology screening assays designed to assess the DNA damaging potential of chemicals in early drug development aiding the identification of promising drugs that have low-risk potential for causing genetic damage contributing to cancer risk in humans. Despite this, in vitro tests generate a high number of misleading positives, the consequences of which can lead to unnecessary animal testing and/or the abandonment of promising drug candidates. Understanding chemical Mode of Action (MoA) is vital to identifying the true genotoxic potential of substances and, therefore, the risk translation into the clinic. Here we demonstrate a simple, robust protocol for staining fixed, human-lymphoblast p53 proficient TK6 cells with antibodies against ɣH2AX, p53 and pH3S28 along with DRAQ5™ DNA staining that enables analysis of un-lysed cells via microscopy approaches such as imaging flow cytometry. Here, we used the Cytek® Amnis® ImageStream®X Mk II which provides a high-throughput acquisition platform with the sensitivity of flow cytometry and spatial morphological information associated with microscopy. Using the ImageStream manufacturer's software (IDEAS® 6.2), a masking strategy was developed to automatically detect and quantify micronucleus events (MN) and characterise biomarker populations. The gating strategy developed enables the generation of a template capable of automatically batch processing data files quantifying cell-cycle, MN, ɣH2AX, p53 and pH3 populations simultaneously. In this way, we demonstrate how a multiplex system enables DNA damage assessment alongside MN identification using un-lysed cells on the imaging flow cytometry platform. As a proof-of-concept, we use the tool chemicals carbendazim and methyl methanesulphonate (MMS) to demonstrate the assay's ability to correctly identify clastogenic or aneugenic MoAs using the biomarker profiles established.

Keywords: Biomarker; DNA damage; ImageStream; Micronucleus; MoA; NAM

DOI: https://doi.org/10.1007/s00204-024-03801-7

Transl Cancer Res. 2024 Jun 30. 13(6): 3075-3089

Combining non-invasive liquid biopsy and a methylation analysis to assess surgical risk for early esophageal cancer.

Xiaole Chen, Mingyan Li, Yongliang Li, Alberto Aiolfi, Luigi Bonavina, Toni Lerut, Xiuxia Wu, Qinsheng Zhang.

Background: While the widespread use of endoscopic submucosal dissection (ESD) has significantly reduced the incidence of early esophageal cancer (ESCA), the limited ability of ESD to strip deep infiltrating esophageal lesions results in a considerable risk of intraoperative perforation. Circulating-free DNA (cfDNA) is widely used in modern tumor screening due to its non-invasive detection capabilities. A methylation analysis offers vital insights into the condition and advancement of malignancies due to its unique positioning, such as a marker of cancer. This study investigated the potential of combining a non-invasive liquid biopsy technique, along with a methylation analysis, to assess the surgical perforation risk of ESCA patients.
Methods: In this study, we conducted an analysis of gene expression differences between stage I esophageal squamous carcinoma samples and healthy tissue samples using data from The Cancer Genome Atlas (TCGA) database. We also identified the genes associated with progression-free survival (PFS) in esophageal squamous carcinoma. Integrating the framework of the methylation analysis, we explored the methylated sites of these distinct genes. To refine this process, we used the Shiny Methylation Analysis Resource Tool (SMART) to conduct a comprehensive analysis of these sites. We then confirmed the stability of the methylation sites in different lesion conditions using methylation-specific quantitative polymerase chain reaction (MS-qPCR) with paraffin tissue samples collected after ESD.
Results: We analyzed RNA-sequencing data from 42 early stage ESCA patients and 17 controls, identifying 1,263 up-regulated and 460 down-regulated genes. Functional analyses revealed involvement in key pathways such as cell cycle regulation and immune responses. Furthermore, we identified 38 differentially expressed genes associated with PFS. Using SMART analysis, we found 217 hyper-methylated regions in 38 genes, suggesting potential early markers for ESCA. Validation experiments confirmed the reliability of 29 hyper-methylated regions in FFPE tissue samples and 6 regions in cfDNA. A LunaCAM model showed high accuracy [area under the curve (AUC) =0.89] in discriminating early ESCA. Integrated assessment of six highly methylated regions significantly improved predictive performance, with 90.56% sensitivity, highlighting the importance of combinatorial biomarker evaluation for early cancer detection.
Conclusions: This study established a novel approach that integrates non-invasive testing with a methylation analysis to assess the surgical risk of early ESCA patients. The significance of changes in methylation sites in relation to lesion status should not be underestimated, as they have the potential to offer vital insights for proactive risk assessments before surgery.

Keywords: Liquid biopsy; esophageal cancer (ESCA); methylation analysis; non-invasive testing

DOI: https://doi.org/10.21037/tcr-24-314

Front Immunol. 2024 ;15 1420847

Integrating single-cell and spatial transcriptomic analysis to unveil heterogeneity in high-grade serous ovarian cancer.

Haixia Luo, Kunyu Wang, Bin Li.

High-grade serous ovarian cancer (HGSOC) presents significant challenges due to its heterogeneity and late-stage diagnoses. Using single-cell and spatial transcriptomics to elucidate the complex landscape of HGSOC to understand its underlying mechanism. Our analysis reveals significant inter- and intra-tumoral diversity, manifested through distinct cellular subpopulations and varied microenvironmental niches. Notably, our findings highlight a widespread immunosuppressive environment, marked by complex networks of cell-cell interactions, particularly evident in areas of elevated tumor cell density within metastatic samples. We identify the exclusive presence of COL14A1+ neoplastic cells in metastatic specimens, alongside a strong correlation between CD8A+ NKT cells and poor prognosis, and elevated CHODL expression in HGSOC metastasis tissues. Furthermore, knockdown experiments targeting CHODL demonstrate its role in reducing migration and invasion abilities in HGSOC cells. A pivotal discovery of our study is the delineation of specific cellular signatures correlated with adverse outcomes, notably a subset of CHODL+ neoplastic cells characterized by a distinct metabolic phenotype with a predilection for lipid metabolism. The therapeutic targeting of this metabolic pathway with existing inhibitors appears promising in curbing tumor proliferation. These findings enhance our understanding of HGSOC heterogeneity and reveal potential therapeutic targets, promising more effective management strategies for this aggressive cancer subtype.

Keywords: CHODL; HGSOC; heterogeneity; multi-omics; spatial transcriptomic

DOI: https://doi.org/10.3389/fimmu.2024.1420847