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The traditional perception of ribosomes as uniform molecular machines has been revolutionized by recent discoveries, revealing a complex landscape of ribosomal heterogeneity. Opposing the conventional belief in interchangeable ribosomal entities, emerging studies underscore the existence of specialized ribosomes, each possessing unique compositions and functions. Factors such as cellular and tissue specificity, developmental and physiological states, and external stimuli, including circadian rhythms, significantly influence ribosome compositions. For instance, muscle cells and neurons are characterized by distinct ribosomal protein sets and dynamic behaviors, respectively. Furthermore, alternative forms of ribosomal RNA (rRNAs) and their post-transcriptional modifications add another dimension to this heterogeneity. These variations, orchestrated by spatial, temporal, and conditional factors, enable the manifestation of a broad spectrum of specialized ribosomes, each tailored for potentially distinct functions. Such specialization not only impacts mRNA translation and gene expression but also holds significant implications for broader biological contexts, notably in the realm of cancer research. As the understanding of ribosomal diversity deepens, it also paves the way for exploring novel avenues in cellular function and offers a fresh perspective on the molecular intricacies of translation. [ABSTRACT FROM AUTHOR]

Simple Summary: Extracellular vesicles (EVs), consisting of microvesicles and exosomes, serve as messengers for intercellular communication by transporting proteins and nucleic acids. In solid cancers of epithelial origin, Epidermal Growth Factor Receptor (EGFR) plays a pivotal role as a driver. In vitro studies conducted on EGFR-dependent solid tumours revealed the significant correlation between EGFR and EVs production, leading to the dissemination of EGFR itself and related molecules along with inducing cell proliferation, modifying the tumour microenvironment, facilitating metastases, and conferring resistance to treatments. Recently, liquid biopsy approaches started to exploit the interplay of EGFR and EVs in delivering proteins, RNAs, and DNAs via blood/plasma of EGFR-dependent tumour patients to evaluate their possible roles and applications as candidate biomarkers in diagnosing and monitoring tumour progression and therapy efficacy. Extracellular vesicles (EVs) are of great interest to study the cellular mechanisms of cancer development and to diagnose and monitor cancer progression. EVs are a highly heterogeneous population of cell derived particles, which include microvesicles (MVs) and exosomes (EXOs). EVs deliver intercellular messages transferring proteins, lipids, nucleic acids, and metabolites with implications for tumour progression, invasiveness, and metastasis. Epidermal Growth Factor Receptor (EGFR) is a major driver of cancer. Tumour cells with activated EGFR could produce EVs disseminating EGFR itself or its ligands. This review provides an overview of EVs (mainly EXOs and MVs) and their cargo, with a subsequent focus on their production and effects related to EGFR activation. In particular, in vitro studies performed in EGFR-dependent solid tumours and/or cell cultures will be explored, thus shedding light on the interplay between EGFR and EVs production in promoting cancer progression, metastases, and resistance to therapies. Finally, an overview of liquid biopsy approaches involving EGFR and EVs in the blood/plasma of EGFR-dependent tumour patients will also be discussed to evaluate their possible application as candidate biomarkers. [ABSTRACT FROM AUTHOR]

The article offers information on IL-1 associated post senescence reprogramming impairs response to EGFR neutralization. Topics include information on tumor heterogeneity and cell plasticity; role of drug pressure; and how pro-inflammatory environments often trigger cellular stress activating sense- cence programs.

Colorectal cancer (CRC) develops over several years, thus, early diagnosis and prevention are fundamental to reduce CRC burden. A new non-invasive blood test based on 4 mRNAs encompassing adhesion molecules such as CEACAM6, as well as a member of the collagen I superfamily, namely COL1A2, combined with LGALS4 and TSPAN8, was recently discovered and referred to as CELTIC panel [1]. The expression of the CELTiC panel was measured by quantitative PCR. The panel of putative biomarkers was subsequently evaluated in 101 subjects resulted positive to fecal immunochemical screening test (FIT) highlighting the potential to distinguish colonoscopy negative-FIT positive patients (NFIT, n=36), patients with low risk lesions (LR, n=36) and with high risk lesions or CRC (HR/CRC, n=92) [2]we searched for mRNA blood markers (CELTiC panel. In this study 174 healthy FIT negative subjects (FITN) were analysed [3] and compared to previous groups, evaluating also the influence of age and sex. Within the FITN group, CEACAM6 and COL1A2 display significantly lower expression in female than in male, confirming this sex difference of CEACAM6, a differentiation marker in normal colonocytes, also in the older groups (60-70 y.o.) and supporting current data on the importance of gender- and age-specific reference intervals for the early diagnosis of CRC [4,5]. The four genes showed significantly lower expression in FITN than in HR/CRC. Interestingly, TSPAN8 and COL1A2 were significantly lower expressed in FITN also than in NFIT and LR patients. TSPAN8, an integral membrane protein which upregulation promotes metastasis [6], was confirmed by logistic model as able to discriminate FITN from NFIT, LR and HR/CRC. Interestingly, also LGALS4, involved in cell-cell interaction and studied in CRC patients [7,8], was able to differentiate FITN from NFIT (false FIT positive). TSPAN8 and galectins have been described also in exosomes [9] suggesting the origin of the mRNAs of the CELTiC panel. Finally, the CELTIC panel showed good sensitivity (84-90%), specificity (76-81%) and AUC (0.87-0.89) to discriminate FITN from the other groups. The CELTiC panel was confirmed as a useful tool to diagnose CRC highlighting the importance of sex and age. A multicenter cross-sectional study will enroll 800 FIT positive subject at the Universities of Amsterdam and Bologna to better estimates the performances of the CELTiC panel and to further validate its robustness and usefulness in the early diagnosis of CRC and to exclude false FIT positive subjects. [ABSTRACT FROM AUTHOR]

The article presents a study on MET-YAP1 interplay at the foundation of perinuclear actin fibers remodeling. Topics include information on a cytoskeletal structure, engaging a subset of apical contractile actin bundles known as stress fibers; regulation of the nuclear shape and cellular motility; and information on mesenchymal-to-epithelial transition factor receptor (MET).

IL-1 belongs to a family of 11 members and is one of the seven receptor-agonists with pro-inflammatory activity. Beyond its biological role as a regulator of the innate immune response, IL-1 is involved in stress and chronic inflammation, therefore it is responsible for several pathological conditions. In particular, IL-1 is known to exert a critical function in malignancies, influencing the tumor microenvironment and promoting cancer initiation and progression. Thus, it orchestrates immunosuppression recruiting pro-tumor immune cells of myeloid origin. Furthermore, new recent findings showed that this cytokine can be directly produced by tumor cells in a positive feedback loop and contributes to the failure of targeted therapy. Activation of anti-apoptotic signaling pathways and senescence are some of the mechanisms recently proposed, but the role of IL-1 in tumor cells refractory to standard therapies needs to be further investigated. [ABSTRACT FROM AUTHOR]

Evidences of a crosstalk between Epidermal Growth Factor Receptor (EGFR) and Glucocorticoid Receptor (GR) has been reported, ranging from the modulation of receptor levels or GR mediated transcriptional repression of EGFR target genes, with modifications of epigenetic markers. The present study focuses on the involvement of EGFR positive and negative feedback genes in the establishment of cetuximab (CTX) resistance in metastatic Colorectal Cancer (CRC) patients. We evaluated the expression profile of the EGFR ligands TGFA and HBEGF, along with the pro-inflammatory cytokines IL-1B and IL-8, which were previously reported to be negatively associated with monoclonal antibody response, both in mice and patient specimens. Among EGFR negative feedback loops, we focused on ERRFI1, DUSP1, LRIG3, and LRIG1. We observed that EGFR positive feedback genes are increased in CTX-resistant cells, whereas negative feedback genes are reduced. Next, we tested the expression of these genes in CTX-resistant cells upon GR modulation. We unveiled that GR activation leads to an increase in ERRFI1, DUSP1, and LRIG1, which were shown to restrict EGFR activity, along with a decrease in the EGFR activators (TGFA and IL-8). Finally, in a cohort of xenopatients, stratified for response to cetuximab, we observed an inverse association between the expression level of LRIG1 and CRC progression upon CTX treatment. Our model implies that combining GR modulation to EGFR inhibition may yield an effective treatment strategy in halting cancer progression. [ABSTRACT FROM AUTHOR]

Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous study on CRC xenopatients associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including the interleukins IL-1A, IL-1B and IL-8. Stemming from these observations, our current work aimed to assess the role of IL-1 pathway activity in CTX resistance. We employed a recombinant decoy TRAP IL-1, a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of the IL-1-receptor (IL-1R1), able to sequester IL-1 directly from the medium. We generated stable clones expressing and secreting a functional TRAP IL-1 into the culture medium. Our results show that IL-1R1 inhibition leads to a decreased cell proliferation and a dampened MAPK and AKT axes. Moreover, CRC patients not responding to CTX blockage displayed higher levels of IL-1R1 than responsive subjects, and abundant IL-1R1 is predictive of survival in patient datasets specifically for the consensus molecular subtype 1 (CMS1). We conclude that IL-1R1 abundance may represent a therapeutic marker for patients who become refractory to monoclonal antibody therapy, while inhibition of IL-1R1 by TRAP IL-1 may offer a novel therapeutic strategy. [ABSTRACT FROM AUTHOR]