Microenvironmental Factors Research Articles

Breast pericytes: a newly identified driver of tumor cell proliferation

IntroductionEffective treatment of breast cancer remains a formidable challenge, partly due to our limited understanding of the complex microenvironmental factors that contribute to disease pathology. Among these factors are tissue-resident perivascular cells, which play crucial roles in shaping vascular basement membranes, maintaining vessel integrity, and communicating with adjacent endothelial cells. Despite their essential functions, perivascular cells have been relatively overlooked. Identifying them by immunostaining has been challenging due to their low abundance, inherent heterogeneity, and shared marker expression with other cell types. These challenges have hindered efforts to purify pericytes and generate primary cell models for studying their biology.MethodsUsing a recently developed FACS method, we successfully identified and purified each cell type from breast tissues, allowing us to deep-sequence their transcriptomes and generate primary cell models of each cell type—including pericytes. Here, we used these data to analyze cell-type-specific gene expression in tumors, which revealed a strong association between pericyte-specific genes and breast cancer patient mortality. To explore this association, we defined the heterogeneity of breast pericytes using single-cell RNA sequencing and identified a broad marker for visualizing perivascular cells in breast tumors.ResultsRemarkably, we discovered perivascular cells dissociated from vessels and emerged as a dominant mesenchymal cell type in a subset of breast tumors that contrasted with their normal perivascular location. Moreover, when we purified pericytes from the breast and cultured them alongside breast tumor cells, we discovered that they induced rapid tumor cell growth significantly greater than isogenic fibroblast controls.DiscussionThese findings identify perivascular cells as a key microenvironmental factor in breast cancer, highlighting the critical need for further research to explore their biology and identify specific stimulatory mechanisms that could be targeted therapeutically.

Recent Advances in Micro/Nanomotor for the Therapy and Diagnosis of Atherosclerosis.

Atherosclerotic cardiovascular disease poses a significant global public health threat with a high incidence that can result in severe mortality and disability. The lack of targeted effects from traditional therapeutic drugs on atherosclerosis may cause damage to other organs and tissues, necessitating the need for a more focused approach to address this dilemma. Micro/nanomotors are self-propelled micro/nanoscale devices capable of converting external energy into autonomous movement, which offers advantages in enhancing penetration depth and retention while increasing contact area with abnormal sites, such as atherosclerotic plaque, inflammation, and thrombosis, within blood vessel walls. Recent studies have demonstrated the crucial role micro/nanomotors play in treating atherosclerotic cardiovascular disease. Hence, this review highlights the recent progress of micro/nanomotor technology in atherosclerotic cardiovascular disease, including the effective promotion of micro/nanomotors in the circulatory system, overcoming hemorheological barriers, targeting the atherosclerotic plaque microenvironment, and targeting intracellular drug delivery, to facilitate atherosclerotic plaque localization and therapy. Furthermore, we also describe the potential application of micro/nanomotors in the imaging of vulnerable plaque. Finally, we discuss key challenges and prospects for treating atherosclerotic cardiovascular disease while emphasizing the importance of designing individualized management strategies specific to its causes and microenvironmental factors.

Canine Adipose-Derived Mesenchymal Stromal Cells Reduce Cell Viability and Migration of Metastatic Canine Oral Melanoma Cell Lines In Vitro

Canine oral melanoma (COM) is a promising target for immunomodulatory therapies aimed at enhancing the immune system’s antitumor response. Given that adipose-derived mesenchymal stem cells (Ad-MSCs) possess immunomodulatory properties through cytokine release, we hypothesized that co-culturing Ad-MSCs and canine peripheral blood mononuclear cells (PBMCs) could stimulate interleukin (IL) production against melanoma cell lines (MCCLs) and help identify therapeutic targets. This study evaluated IL-2, IL-8, and IL-12 expressions in co-culture with MCCL, Ad-MSCs, and PBMCs and assessed the relationship between gene expression, cell viability, and migration. Using four experimental groups in a Transwell insert system to separate cell types, we found that Ad-MSCs can reduce MCCL migration and viability, though the effect may vary depending on each cell line’s susceptibility. Furthermore, Ad-MSCs modified IL expression profiles in co-cultured cells. Our findings suggest that Ad-MSCs could have therapeutic potential for COM by inhibiting cell migration and reducing viability. However, deeper insights into Ad-MSC interactions with the tumor microenvironment and melanoma-specific factors will be essential to optimize therapeutic efficacy.

Progress in the study of metastatic mechanism of colorectal cancer in vivo

The main object of this paper is colorectal cancer (CRC). Colorectal cancer is a malignant tumor that occurs in the colon or rectum. It is one of the most common cancers in the digestive system in the world. Its pathogenesis is complex and is related to many factors, including genetic factors and lifestyle habits. Mild cases can be treated and have a high probability of recovery, but severe tumors can even be fatal. For CRC, this paper includes its pathogenesis, metastasis mechanism, and corresponding intervention measures. Through research on these aspects, it aims to have a more comprehensive understanding of the causes, development process, and treatment strategies of CRC. The pathogenesis of CRC is usually affected by many different factors. This article will mainly discuss the factors of genetics, diet, and lifestyle. In terms of metastasis mechanism, tumor immune microenvironment, epithelial-mesenchymal transition (EMT), and vascular growth factors play a decisive and key role. Then this article also discusses intervention measures for CRC, including inhibiting the formation of new blood vessels, immunotherapy, and the use of chemotherapy agents.

Advances in Understanding Drug Resistance Mechanisms and Innovative Clinical Treatments for Melanoma.

Melanoma, a highly invasive skin cancer resulting from melanocyte malignant transformation, is the third most common skin malignancy. Despite accounting for only 4% to 5% of all skin malignancies, it is responsible for 80% of skin cancer-related deaths. Targeted therapies and immune checkpoint inhibitors have improved survival rates, yet drug resistance remains a major challenge. In this review, I explore the latest research progress on melanoma drug resistance mechanisms and clinical treatment methods. This aims to provide insights for more effective treatment strategies and improve patient prognosis and quality of life. I also discuss potential strategies to overcome drug resistance based on the latest scientific findings, with a particular focus on the complex and multi-factorial drug resistance mechanisms of melanomas, including genetic mutations, epigenetic changes, and tumor microenvironment factors. Understanding these mechanisms is crucial for developing new drugs and combination therapies targeting drug-resistant tumors. Analyzing complex drug resistance pathways paves the way for personalized medical approaches, which is expected to provide enlightenment on breaking through drug resistance barriers and enhancing the effectiveness of melanoma treatment.

Honing CAR T cells to tackle acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a dismal disease with poor prognosis, particularly in the relapsed/refractory (r/r) setting. Chimeric antigen receptor (CAR) therapy has yielded remarkable clinical results in other leukemias and thus has, in principle, the potential to achieve similar outcomes in r/r AML. Re-directing the approved CD19-specific CAR designs against the myeloid antigens CD33, CD123 or CLEC12A has occasionally yielded morphological leukemia-free states (MLFS) but has so far been marred by threatening myeloablation and early relapses. These safety and efficacy limitations owe in large part to the challenge of identifying suitable target antigens and designing adequate receptors for effective recognition and safe elimination of AML. Building on lessons learned from the initial clinical attempts, a new wave of CAR strategies relying on alternative target antigens and innovative CAR designs is about to enter clinical evaluation. Adapted multi-antigen targeting, logic-gating and emerging cell engineering solutions offer new possibilities to better direct T cell specificity and sensitivity towards AML. Pharmacologic modulation and genetic epitope engineering may extend these approaches by augmenting target expression in AML cells or minimizing target expression in normal hematopoietic cells. On/off switches or CAR T cell depletion may curb excessive or deleterious CAR activity. Investigation of AML-intrinsic resistance and leukemic microenvironmental factors is poised to reveal additional targetable AML vulnerabilities. We summarize here the findings, challenges and new developments of CAR therapy for AML. These illustrate the need to specifically adapt CAR strategies to the complex biology of AML to achieve better therapeutic outcomes.

A chimeric peptide promotes immune surveillance of senescent cells in injury, fibrosis, tumorigenesis and aging.

The accumulation of senescent cells can lead to tissue degeneration, chronic inflammatory disease and age-related tumorigenesis. Interventions such as senolytics are currently limited by off-target toxicity, which could be circumvented by instead enhancing immune-mediated senescent cell clearance; however, immune surveillance of senescent cells is often impeded by immunosuppressive factors in the inflammatory microenvironment. Here, we employ a chimeric peptide as a 'matchmaker' to bind to the urokinase-type plasminogen activator receptor, a cell surface marker of senescent cells. This peptide modifies the cell surface with polyglutamic acid, promoting immune cell-mediated responses through glutamate recognition. By enhancing the recruitment of immune cells and directly coupling senescent cells and immune cells, we show that this chimeric peptide induces immune clearance of senescent cells and restores tissue homeostasis in conditions such as liver fibrosis, lung injury, cancer and natural aging in mice. This chimeric peptide introduces an immunological conversion strategy that rebalances the senescent immune microenvironment, offering a promising direction for aging immunotherapy.

Gene and protein expression of inflammatory and tissue remodelling factors in the colon adenocarcinoma microenvironment

Gene and protein expression of inflammatory and tissue remodelling factors in the colon adenocarcinoma microenvironment

Small cell lung cancer with liver metastases: from underlying mechanisms to treatment strategies.

Small cell lung cancer (SCLC) represents an aggressive neuroendocrine (NE) tumor within the pulmonary region, characterized by very poor prognoses. Druggable targets for SCLC remain limited, thereby constraining treatment options available to patients. Immuno-chemotherapy has emerged as a pivotal therapeutic strategy for extensive-stage SCLC (ES-SCLC), yet it fails to confer significant efficacy in cases involving liver metastases (LMs) originating from SCLC. Therefore, our attention is directed towards the challenging subset of SCLC patients with LMs. Disease progression of LM-SCLC patients is affected by various factors in the tumor microenvironment (TME), including immune cells, blood vessels, inflammatory mediators, metabolites, and NE substances. Beyond standard immuno-chemotherapy, ongoing efforts to manage LMs in SCLC encompass anti-angiogenic therapy, radiotherapy, microwave ablation (MWA) / radiofrequency ablation (RFA), trans-arterial chemoembolization (TACE), and systemic therapies in conjunction with local interventions. Prospective experimental and clinical investigations into SCLC should prioritize precise and individualized approaches to enhance the prognosis across distinct patient cohorts.

Proteogenomic analysis reveals non-small cell lung cancer subtypes predicting chromosome instability, and tumor microenvironment

Non-small cell lung cancer (NSCLC) is histologically classified into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LSCC). However, some tumors are histologically ambiguous and other pathophysiological features or microenvironmental factors may be more prominent. Here we report integrative multiomics analyses using data for 229 patients from a Korean NSCLC cohort and 462 patients from previous multiomics studies. Histological examination reveals five molecular subtypes, one of which is a NSCLC subtype with PI3K-Akt pathway upregulation, showing a high proportion of metastasis and poor survival outcomes regardless of any specific NSCLC histology. Proliferative subtypes are present in LUAD and LSCC, which show strong associations with whole genome doubling (WGD) events. Comprehensive characterization of the immune microenvironment reveals various immune cell compositions and neoantigen loads across molecular subtypes, which predicting different prognoses. Immunological subtypes exhibit a hot tumor-enriched state and a higher efficacy of adjuvant therapy.

Systemic drug repurposing for pancreatic cancer based on genetic and epigenetic network analysis using a systems biology approach and deep neural learning of drug-target interactions

Pancreatic cancer is a malignant tumor associated with a high mortality rate. This research presents a systems biology approach to explore the mechanisms of pancreatic ductal adenocarcinoma (PDAC), aiming to identify significant biomarkers that can serve as drug targets. We propose a systematic drug repurposing strategy that incorporates a deep neural network (DNN)-based drug-target interaction (DTI) model along with drug design specifications to develop a potential multi-molecule drug for PDAC treatment. We first established candidate protein-protein interaction networks and gene regulatory networks using big data mining techniques. Real PDAC and non-PDAC genome-wide genetic and epigenetic networks (GWGENs) were systematically identified using their corresponding microarray data through system identification and system order detection methods. The top 6,000 core GWGENs of PDAC and non-PDAC were extracted using the Principal Network Projection method. Subsequently, we annotated the core GWGENs using the Kyoto Encyclopedia of Genes and Genomes pathways to construct their respective core signaling pathways. By comparing upstream microenvironmental factors, core signaling pathways, and downstream aberrant cellular functions between PDAC and non-PDAC, we investigated the carcinogenic mechanisms of PDAC. Notably, c-MYC, forkhead box O3, and tumor suppressor p53 were identified as significant biomarkers for potential drug targets. Furthermore, the DNN-based DTI model predicted the interaction probabilities between candidate molecular drugs and these biomarkers. Based on drug design specifications such as regulatory ability, sensitivity, and toxicity, suitable multi-molecular potential drugs were selected. Ultimately, gemcitabine and MK-2206 were identified as a promising multi-molecular drug combination for PDAC treatment.

Multilevel Mechanisms of Cancer Drug Resistance.

Cancer drug resistance represents one of the most significant challenges in oncology and manifests through multiple interconnected molecular and cellular mechanisms. Objective: To provide a comprehensive analysis of multilevel processes driving treatment resistance by integrating recent advances in understanding genetic, epigenetic, and microenvironmental factors. This is a systematic review of the recent literature focusing on the mechanisms of cancer drug resistance, including genomic studies, clinical trials, and experimental research. Key findings include the following: (1) Up to 63% of somatic mutations can be heterogeneous within individual tumors, contributing to resistance development; (2) cancer stem cells demonstrate enhanced DNA repair capacity and altered metabolic profiles; (3) the tumor microenvironment, including cancer-associated fibroblasts and immune cell populations, plays a crucial role in promoting resistance; and (4) selective pressure from radiotherapy drives the emergence of radioresistant phenotypes through multiple adaptive mechanisms. Understanding the complex interplay between various resistance mechanisms is essential for developing effective treatment strategies. Future therapeutic approaches should focus on combination strategies that target multiple resistance pathways simultaneously, guided by specific biomarkers.

Abstract B019: Regulatory macrophages contribute to tumor cell plasticity in colorectal cancer metastases

Abstract Metastatic disease is the common cause of death in colorectal cancer. To better understand the cellular landscape of colorectal metastasis, we profiled primary tumors and liver, lung, and peritoneal metastases using single-cell RNA sequencing. Our analysis revealed a subset of tumor epithelial cells with a highly plastic transcription profile and, inversely, low expression of stemness markers. Tumor cells with plasticity markers were spatially enriched at the tumor- stroma interface with exposure to tissue microenvironmental factors. Cell-free malignant ascites, which recapitulates the tumor microenvironment, impaired expression of proliferation and stem- like markers in favor of plasticity markers and enhanced migration of tumor cells. Furthermore, Co-culture of colorectal tumor cells with CD11b+ macrophages isolated from malignant ascites from patients was sufficient to recapitulate tumor cell plasticity. Profiling of tumor-associated macrophages identified enrichment for a lipid-handling features and high spatial correlation with plastic tumor cells. Taken together, we demonstrate that tumor-associated macrophages contribute to disease progression through development of pro-malignant features. Citation Format: Matthew A. Cottam, Muhammad B. Mirza, Emily N. Arner, Marium Siddiqui, Clare Lipscombe, Zaid Hatem, Katy E. Beckermann, Kamran Idrees. Regulatory macrophages contribute to tumor cell plasticity in colorectal cancer metastases [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B019.

Nutritional Status and Anemia among Scheduled Caste Adolescent Girls of District Yamunanagar, Haryana, India

Background: During adolescence, nutrition is crucial for physical and cognitive development, yet socio-economic disparities and nutritional deficiencies, especially in girls, lead to health vulnerabilities, including high anemia rates. Despite recent data from the National Family Health Survey, there is limited information on adolescents aged 11-16 years, requiring targeted research. This cross-sectional study aims to assess the nutritional status, determine the prevalence of anemia, and explore associated factors among adolescent girls of the scheduled caste in District Yamunanagar, Haryana, India. Methods: The study sampled 450 scheduled caste girls aged 11-16 years from schools in District Yamunanagar, Haryana. Height and weight were measured to calculate Body Mass Index (BMI). Data on micro-environmental factors, socio-economic and demographic variables, and dietary habits were collected through interview-based schedule. Hemoglobin levels were measured using Sahli’s Acid Haematin technique, and nutritional status was assessed using the World Health Organization (WHO) standards (Z-score method). Results: The study found increases in height, weight, and BMI with age, with notable spurts at 12-13 years for height and 11-12 years for weight and BMI. Significant differences in height, weight, and BMI were observed between age groups. Moreover, 92.2% girls were found to be anemic, with most of them suffering from moderate anemia. Additionally, the prevalence of stunting was 67.33% and wasting was 64.90% among the girls. Household size, number of family members and menarcheal status of the girls showed a significant association with the nutritional status and anemic of the girls. Conclusion: The study emphasizes the need of regular screening and timely interventions to improve the nutritional and anemic status of adolescent girls.

Abstract B069: Spatial and single-cell proteomic landscaping of the hypoxic microenvironment in glioblastoma

Abstract Glioblastoma (GBM) is a fatal adult solid tumour with median overall survival of 18-20 months post-diagnosis; contributing factors to therapeutic inefficacy include acquisition of genomic alterations post-therapy, immune evasion, deregulated hypervascularization, and tumor microenvironmental factors such as hypoxia. Combined with extensive inter- and intra-tumoral heterogeneity at bulk and single-cell level, hypoxia contributes to a gradient of molecular alterations that are specific to different cell populations that make up tumour bulk and reside in specific niches. Hitherto, high-dimensional histopathologic analyses of hypoxic regions within GBM tissue have not been performed. We took a combined spatial and single-cell proteomic profiling approach to investigate the histopathologic features of hypoxia by leveraging a unique clinical study wherein the exogenous hypoxia marker, pimonidazole (PIMO), was administered to GBM-patients preoperatively. Tissue specimens were subjected to imaging mass cytometry, high-resolution imaging, and serial immunohistochemistry using a panel of markers associated with cellular hallmarks of hypoxia, metabolism, proliferation, stemness, angiogenesis, and immune cell types. Our findings showed that PIMO staining is associated with histopathologic features of hypoxia and correlates with specific metabolic, immune, and stemness markers in GBM; specific lymphocyte populations were depleted from hypoxic regions alongside alterations in macrophagic and microglial landscape in a niche-specific manner; hypoxia reduced the proportion of proliferating glioma initiating cells and altered the proliferative, transcriptional, and translational capacity of different cell populations; microvessel density was reduced in hypoxic microenvironment. Cytometry by time-of-flight further validated the altered proportions of specific immune cell types enriched in hypoxic populations of GBM microenvironment. Our study is the first to report use of PIMO to interrogate spatial, single-cell, and phenotypic architecture associated with tissue hypoxia and altered expression of biomarkers associated with hypoxia/glycolysis, immune infiltration, proliferation, and stemness. Identification of targetable biomarkers and mediators of hypoxia-driven habitats in GBM may provide direction for future immunotherapeutic research. Citation Format: Shreya Gandhi, Sheila Mansouri, Olivia Singh, Mark Zaidi, Ronald Wu, Andrew Gao, Bradley Wouters, Gelareh Zadeh. Spatial and single-cell proteomic landscaping of the hypoxic microenvironment in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B069.

EPCO-16. METHOD TO MODEL AND CORRECT NOISE IN SINGLE-NUCLEI RNA-SEQUENCING DATA FROM POST-MORTEM BRAIN

Abstract Post-mortem brain samples are crucial for neuropathological research. For brain cancers, they provide insights about disease progression, microenvironmental factors, and treatment resistance. In some brain diseases, brain tissue may only be available post-mortem. Establishing a reference atlas of healthy brain also requires post-mortem donations. Beyond logistical and ethical challenges of post-mortem samples, there are also post-mortem factors that mask biological signal. In this study, we specifically aim to model post-mortem gene expression changes in single-nuclei RNA-sequencing (snRNA-seq) data. We analyze a public snRNA-seq dataset of pediatric high-grade glioma (pHGG) that has matched samples at initial resection and autopsy. We find a clear gene signature, composed of mitochondrial genes, stress-related genes, and metabolism-related genes, that is upregulated post-mortem. This signature also appears in post-mortem snRNA-seq data from other brain diseases and healthy donors. We classify it as “post-mortem noise”. We model the post-mortem noise as a combination of technical and biological artifact. The technical artifact is correlated with the percentage of mitochondrial reads and is a general measure of sample quality. The biological artifact is correlated with post-mortem interval and represents gene expression changes due to post-mortem stress. We apply our model to the pHGG data by regressing out the technical and biological artifact. Removing the post-mortem noise results in an improvement in malignant versus normal cell prediction, cell type classification, and the uncovering of pathways related to glioma progression. We confidently identify several normal cell types and predict their interactions with cancer cells, highlighting the utility of wider possible margins post-mortem. Therefore, after removing post-mortem noise, we analyze glioma progression at an unparalleled timepoint and characterize late-stage changes in the tumor microenvironment. In conclusion, we develop a method that models post-mortem noise in snRNA-seq brain data. Our method can be broadly applied to future brain cancer studies using post-mortem tissue.

CNSC-65. ELECTROPHYSIOLOGICAL AND SPATIAL TRANSCRIPTOMIC PROFILING OF GLIOMA-INFILTRATED CORTEX REVEAL LAYER SPECIFIC ALTERATIONS

Abstract Specialized neocortical circuits selectively organize neuronal signals and encode features of cognitive processing via local and long-range connections. Since glioma-infiltrated cortex is excitable and can participate in cognitive processing, the underlying laminar structure and functionality may still be preserved despite infiltration. Moreover, since glioma cells remodel existing neural circuits and microenvironmental factors drive invasion and proliferation, neuron-glioma interactions may demonstrate layer specificity. As glioma-infiltrated cortex remains poorly understood, we sought to characterize these regions using electrophysiological, structural, and genomic approaches. We assessed the power spectra of normal-appearing and glioma-infiltrated cortex using magnetoencephalography and subdural high-density electrode arrays. Immunohistochemistry of formalin-fixed paraffin-embedded (FFPE) samples of infiltrated cortex enabled protein-level neuronal and glioma identification to determine laminar preservation and spatial invasion patterns. Spatial transcriptomics of FFPE tissues and single-nucleus RNA-sequencing were used to identify cell populations, genomic alterations, and cell-cell communication within and across samples at testing and validation sites across the US and Europe. Increased delta range (1-4 Hz) power and decreased power in the beta range (12-20 Hz), activity thought to originate from deep layers, were identified as robust features of infiltrated cortex which were maintained across glioma subtypes (n = 139 patients) and preserved in a validation cohort (n = 8 patients). Immunohistochemistry revealed greater tumor burden within deep laminae regardless of glioma subtype (n = 20 samples). Tissue proteomics and spatial genomics analyses performed using glioma-infiltrated cortical samples (n = 10 samples; 29,011 spots) confirmed routine preservation of laminar organization, greater tumor burden in deep layers, as well as layer specific differences in glioma-related expression programs. Cell-cell communication analyses demonstrated increased interactions in glioma-infiltrated cortex across layers. These findings suggest that laminar structure may be preserved in glioma-infiltrated cortex while remodeling of neural circuits alters spatiotemporal activity in a predictable manner and support a deep to superficial invasion pattern. Thus, investigating glioma infiltration using layer-centric approaches may facilitate novel insights into neuron-glioma interactions.

Discovery of miRNA–mRNA regulatory networks in glioblastoma reveals novel insights into tumor microenvironment remodeling

Adult glioblastoma (GBM) is a highly aggressive primary brain tumor, accounting for nearly half of all malignant brain tumors, with a median survival rate of only 8 months. Treatment for GBM is largely ineffective due to the highly invasive nature and complex tumor composition of this malignancy. MicroRNAs (miRNA) are short, non-coding RNAs that regulate gene expression by binding to messenger RNAs (mRNA). While specific miRNA have been associated with GBM, their precise roles in tumor development and progression remain unclear. In this study, the analysis of miRNA expression data from 743 adult GBM cases and 59 normal brain samples identified 94 downregulated miRNA and 115 upregulated miRNA. Many of these miRNA were previously linked to GBM pathology, confirming the robustness of our approach, while we also identified novel miRNA that may act as potential regulators in GBM. By integrating miRNA predictions with gene expression data, we were able to associate downregulated miRNA with tumor microenvironment factors, including extracellular matrix remodeling and signaling pathways involved in tumor initiation, while upregulated miRNA were found to be associated with essential neuronal processes. This analysis highlights the significance of miRNA in GBM and serves as a foundation for further investigation.

From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression.

This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. Additional molecular alterations in neoplastic cells, including epigenetic modifications and chromosomal alterations, can further contribute to neoplastic progression. In parallel with these alterations in neoplastic cells, the microenvironment, including fibroblast activation, extracellular matrix remodeling, and immune modulation, plays a pivotal role in PanIN initiation and progression. Crosstalk between neoplastic and stromal cells influences nutrient support and immune evasion, contributing to tumor development, growth, and survival. This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.

Impact of Bone Metastasis in Stage IV Non–Small Cell Lung Cancer Treated With Durvalumab and Tremelimumab With or Without Chemotherapy: A Retrospective Analysis of the CCTG BR.34 Trial

PURPOSE This retrospective analysis examines the impact of bone metastasis on outcomes in patients with non–small cell lung cancer (NSCLC) from the CCTG BR.34 trial, which investigated the combined immune checkpoint blockade. MATERIALS AND METHODS The CCTG BR.34 trial was a randomized phase II study assessing durvalumab plus tremelimumab, with or without platinum-doublet chemotherapy, in 301 patients with metastatic NSCLC. Patients were categorized into two cohorts on the basis of bone metastasis: cohort A (n = 129) and cohort B (n = 172). The primary end point was overall survival (OS), analyzed using Cox regression and multivariable models. RESULTS Patients with bone metastasis had notably poorer outcomes. The median OS was 10.9 months for those with bone metastasis versus 18.7 months for those without (hazard ratio [HR] 1.68, P = .001). The median progression-free survival (PFS) was 3.4 months with bone metastasis compared with 7.2 months without (HR, 1.82, P < .0001). The overall response rate (ORR) was lower in patients with bone metastasis (29.5%) compared with those without (45.9%; odds ratio [OR], 0.52, P = .01). Adding chemotherapy to durvalumab plus tremelimumab did not significantly affect OS ( P = .23), PFS ( P = .84), or ORR ( P = .25) in relation to bone metastasis. Multivariable analysis reaffirmed that bone metastasis was linked to decreased OS (HR, 1.42, P = .036), PFS (HR, 1.69, P < .0001), and ORR (OR, 0.52, P = .01). CONCLUSION Bone metastasis was associated with worse outcomes in this dual immune checkpoint blockade trial, with or without chemotherapy. Future trials should consider bone metastasis as a stratification factor and explore combining immune checkpoint inhibitors with targeted therapies addressing bone microenvironment factors (eg, interleukin-8, PTHrP, and transforming growth factor-β).