Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma.

Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression.

Dual gene set enrichment analysis (dualGSEA); an R function that enables more robust biological discovery and pre-clinical model alignment from transcriptomics data.

Gene set enrichment analysis (GSEA) tools can identify biological insights within gene expression-based studies. Although their statistical performance has been compared, the downstream biological implications that arise when choosing between the range of pairwise or single sample forms of GSEA methods remain understudied. We compare the statistical and biological results obtained from various pre-ranking methods/options for pairwise GSEA, followed by a stand-alone comparison of GSEA, single sample GSEA (ssGSEA) and gene set variation analysis (GSVA).

Tumor-associated mesenchymal stromal cells modulate macrophage phagocytosis in stromal-rich colorectal cancer via PD-1 signaling.

CMS4 colorectal cancer (CRC), based on the consensus molecular subtype (CMS), stratifies patients with the poorest disease-free survival rates. It is characterized by a strong mesenchymal stromal cell (MSC) signature, wound healing-like inflammation and therapy resistance. We utilized 2D and 3D , and models to assess the impact of inflammation and stromal cells on immunosuppression in CMS4 CRC.

Unveiling impaired vascular function and cellular heterogeneity in diabetic donor-derived vascular organoids.

Vascular organoids (VOs), derived from induced pluripotent stem cells (iPSCs), hold promise as in vitro disease models and drug screening platforms. However, their ability to faithfully recapitulate human vascular disease and cellular composition remains unclear. In this study, we demonstrate that VOs derived from iPSCs of donors with diabetes (DB-VOs) exhibit impaired vascular function compared to non-diabetic VOs (ND-VOs).

Stratification to Neoadjuvant Radiotherapy in Rectal Cancer by Regimen and Transcriptional Signatures.

Unlabelled: Response to neoadjuvant radiotherapy (RT) in rectal cancer has been associated with immune and stromal features that are captured by transcriptional signatures. However, how such associations perform across different chemoradiotherapy regimens and within individual consensus molecular subtypes (CMS) and how they affect survival remain unclear. In this study, gene expression and clinical data of pretreatment biopsies from nine cohorts of primary rectal tumors were combined (N = 826).

Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.

Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5 stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1 stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease.

Molecular pathological classification of colorectal cancer-an update.

Colorectal cancer (CRC) has a broad range of molecular alterations with two major mechanisms of genomic instability (chromosomal instability and microsatellite instability) and has been subclassified into 4 consensus molecular subtypes (CMS) based on bulk RNA sequence data. Here, we update the molecular pathological classification of CRC with an overview of more recent bulk and single-cell RNA data analysis for development of transcriptional classifiers and risk stratification methods, taking into account the marked inter-tumoural and intra-tumoural heterogeneity of CRC. The importance of the stromal and immune components or tumour microenvironment (TME) to prognosis has emerged from these analyses.

Radiation-induced changes in gene expression in rectal cancer specimens.

Purpose: The standard-of-care for locally advanced rectal cancer is radiotherapy-based neoadjuvant therapy followed by surgical resection. This article reviews the evidence of molecular changes at the transcriptome level induced through radiotherapy in rectal cancer.

Methods: The PubMed search "(radiation OR radiotherapy) cancer (transcriptome OR "gene expression") rectal" was used.

PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia.

Ischaemic cardiovascular disease is associated with tissue hypoxia as a significant determinant of angiogenic dysfunction and adverse remodelling. While cord blood-derived endothelial colony-forming cells (CB-ECFCs) hold clear therapeutic potential due to their enhanced angiogenic and proliferative capacity, their impaired functionality within the disease microenvironment represents a major barrier to clinical translation. The aim of this study was to define the specific contribution of NOX4 NADPH oxidase, which we previously reported as a key CB-ECFC regulator, to hypoxia-induced dysfunction and its potential as a therapeutic target.

β-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer.

Intraepithelial lymphocytes (IEL) expressing γδ T-cell receptors (γδTCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immunosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic γδIELs.

Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment.

Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions.

MmCMS: mouse models' consensus molecular subtypes of colorectal cancer.

Background: Colorectal cancer (CRC) primary tumours are molecularly classified into four consensus molecular subtypes (CMS1-4). Genetically engineered mouse models aim to faithfully mimic the complexity of human cancers and, when appropriately aligned, represent ideal pre-clinical systems to test new drug treatments. Despite its importance, dual-species classification has been limited by the lack of a reliable approach.

Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features.

The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC.

Distinct Molecular Profiles of Sporadic Early-Onset Colorectal Cancer: A Population-Based Cohort and Systematic Review.

Background And Aims: The observed increase in the incidence of early-onset colorectal cancer (EOCRC) is being driven by sporadic cases, but the molecular characteristics of these tumors are not fully understood. Our objective was to investigate the prevalence of microsatellite instability (MSI) and selected mutations in sporadic EOCRC, and their association with survival.

Methods: Firstly, we compared the prevalence of molecular characteristics and survival within a population-based cohort study of 652 stage II and III colon cancer patients in Northern Ireland, comparing sporadic early-onset (<50 years, n = 35) with older (60-69 years, n = 179) patients.

Global colorectal cancer research, 2007-2021: Outputs and funding.

The purpose of this study was to provide an evidence base for colorectal cancer research activity that might influence policy, mainly at the national level. Improvements in healthcare delivery have lengthened life expectancy, but within a situation of increased cancer incidence. The disease burden of CRC has risen significantly, particularly in Africa, Asia and Latin America.

Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia.

Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions.

Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data.

Purpose: Precise mechanism-based gene expression signatures (GES) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling.

Spend less to achieve more: Economic analysis of intermittent versus continuous cetuximab in KRAS wild-type patients with metastatic colorectal cancer.

Background: In 2014, the COIN-B clinical trial demonstrated that intermittent cetuximab (IC) was a safe alternative to continuous cetuximab (CC), with less cytotoxic chemotherapy, in first-line treatment for KRAS wild-type metastatic colorectal cancer (mCRC). Cetuximab has been available for this indication in England since 2015, but treatment breaks beyond 6 weeks were prohibited, despite real-world evidence that therapy de-escalation maintains equivalent disease control, but with superior Quality-of-Life (QoL). We performed health economic analyses of IC versus CC and used this evidence to help underpin policy change and guide clinical practice through reduction in unnecessary treatment for mCRC patients.

Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer.

Objective: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy.

Design: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of and stroma-rich models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours.

Molecular Subtyping Resource: a user-friendly tool for rapid biological discovery from transcriptional data.

Generation of transcriptional data has dramatically increased in the past decade, driving the development of analytical algorithms that enable interrogation of the biology underpinning the profiled samples. However, these resources require users to have expertise in data wrangling and analytics, reducing opportunities for biological discovery by 'wet-lab' users with a limited programming skillset. Although commercial solutions exist, costs for software access can be prohibitive for academic research groups.