Cancer Metastatic Potential Research Articles

Multifunctional role of the tumor associated monocytes/macrophages in the metastatic potential of inflammatory breast cancer.

Inflammatory breast cancer (IBC) is the most aggressive and lethal phenotype form of breast cancer, which afflicts young women at high incidence in North Africa compared to other continents of the world. IBC is characterized by highly metastatic behavior and possesses specific pathobiological properties different from non-IBC. IBC disease displays unusual common properties at typical presentation, including positive metastatic lymph-nodes, high infiltration of tumor associated monocytes/macrophages, rapid progression to distant metastasis, and possibly the production of a unique repertoire of growth factors, cytokines and chemokines, as well as a striking association with different polarized macrophages compared to non-IBC. Indeed, tumor associated monocytes/macrophages (TAM/M) play a crucial role in breast cancer development. Previously, we showed that cross talk between IBC cells and patient derived TAMs occurs via secretion of inflammatory mediators from TAMs that act on specific extracellular domain receptors activating down-stream signaling pathways that promote the epithelial-to-mesenchymal transition, cancer cell invasion, IBC stem cell properties, drug resistance, local and metastatic recurrence of residual tumor cells and other key markers of malignancy, including in vitro colony formation capacity. In this mini review, we will discuss the role of TAMs in IBC cancer metastatic potential and molecules involved. The review also discusses the recent discoveries in the field of IBC research.

Protrusion force and cell-cell adhesion play a critical role in collective tumor cluster migration.

While collective migration is shown to enhance invasive and metastatic potential in cancer, the mechanisms driving this behavior and regulating tumor migration plasticity remain poorly understood. This study provides a mechanistic framework explaining the emergence of different modes of collective migration under hypoxia-induced secretome. We focus on the interplay between cellular protrusion force and cell-cell adhesion using collectively migrating three-dimensional microtumors as models with well-defined microenvironment. Large microtumors show directional migration due to intrinsic hypoxia, while small microtumors exhibit radial migration in response to hypoxic secretome. Here, we developed the minimal multi-scale microtumor model (MSMM) to elucidate underlying mechanisms. We identified distinct migration modes within specific regions of protrusion force and cell-cell adhesion parameter space. We show that sufficient cellular protrusion force is crucial for both, radial and directional collective microtumor migration. Radial migration emerges when sufficient cellular protrusion force is generated, driving neighboring cells to move collectively in diverse directions. Within migrating tumors, strong cell-cell adhesion enhances the alignment of cell polarity, breaking the symmetric angular distribution of protrusion forces, and leading to directional microtumor migration. The integrated results from the experimental and computational models provide fundamental insights into collective migration in response to different microenvironment stimuli.

Single-Cell Fluidic Force Spectroscopy Reveals Dynamic Mechanical Fingerprints of Malignancy in Breast Cancer.

The interplay between cancer cell physical characteristics and metastatic potential highlights the significance of cancer cell mechanobiology. Using fluidic-based single-cell force spectroscopy (SCFS), quartz crystal microbalance with dissipation (QCM-D), and a model of cells with a spectrum of metastatic potential, we track the progression of biomechanics across the metastatic states by measuring cell-substrate and cell-to-cell adhesion forces, cell spring constant, cell height, and cell viscoelasticity. Compared to highly metastatic cells, cells in the lower spectrum of metastatic ability are found to be systematically stiffer, less viscoelastic, and larger. These mechanical transformations in cells within a cluster correlate with cells' metastatic potential but are significantly absent in single cells. Additionally, the response to chemotherapy is found to be highly dependent on cell viscoelastic properties in terms of both response time and magnitude. Shifts in cell softness and elasticity might serve as mechanoadaptive mechanisms during cancer cell metastasis, contributing to our understanding of metastasis and the effectiveness of potential therapeutic interventions.

Vimentin-mediated buffering of internal integrin β1 pool increases survival of cells from anoikis

BackgroundThe intermediate filament protein vimentin is widely recognized as a molecular marker of epithelial-to-mesenchymal transition. Although vimentin expression is strongly associated with cancer metastatic potential, the exact role of vimentin in cancer metastasis and the underlying mechanism of its pro-metastatic functions remain unclear.ResultsThis study revealed that vimentin can enhance integrin β1 surface expression and induce integrin-dependent clustering of cells, shielding them against anoikis cell death. The increased integrin β1 surface expression in suspended cells was caused by vimentin-mediated protection of the internal integrin β1 pool against lysosomal degradation. Additionally, cell detachment was found to induce vimentin Ser38 phosphorylation, allowing the translocation of internal integrin β1 to the plasma membrane. Furthermore, the use of an inhibitor of p21-activated kinase PAK1, one of the kinases responsible for vimentin Ser38 phosphorylation, significantly reduced cancer metastasis in animal models.ConclusionsThese findings suggest that vimentin can act as an integrin buffer, storing internalized integrin β1 and releasing it when needed. Overall, this study provides insights regarding the strong correlation between vimentin expression and cancer metastasis and a basis for blocking metastasis using this novel therapeutic mechanism.

Exploring the Role of Clustered Mutations in Carcinogenesis and Their Potential Clinical Implications in Cancer.

Abnormal cell proliferation and growth leading to cancer primarily result from cumulative genome mutations. Single gene mutations alone do not fully explain cancer onset and progression; instead, clustered mutations-simultaneous occurrences of multiple mutations-are considered to be pivotal in cancer development and advancement. These mutations can affect different genes and pathways, resulting in cells undergoing malignant transformation with multiple functional abnormalities. Clustered mutations influence cancer growth rates, metastatic potential, and drug treatment sensitivity. This summary highlights the various types and characteristics of clustered mutations to understand their associations with carcinogenesis and discusses their potential clinical significance in cancer. As a unique mutation type, clustered mutations may involve genomic instability, DNA repair mechanism defects, and environmental exposures, potentially correlating with responsiveness to immunotherapy. Understanding the characteristics and underlying processes of clustered mutations enhances our comprehension of carcinogenesis and cancer progression, providing new diagnostic and therapeutic approaches for cancer.

Mechanistic insights into FEN1-mediated drug sensitivity and risk signature in colon cancer: An integrative bioinformatics study.

The overexpression of Flap endonuclease 1 (FEN1) has been implicated in drug resistance and prognosis across various cancer types. However, the precise role of FEN1 in colon cancer remains to be fully elucidated. In this study, we employed comprehensive datasets from The Cancer Genome Atlas, Gene Expression Omnibus, and Human Protein Atlas to examine FEN1 expression and assess its correlation with clinical pathology and prognosis in colon cancer. We utilized the pRRophetic algorithm to evaluate drug sensitivity and performed differential expression analysis to identify genes associated with FEN1-mediated drug sensitivity. Gene set enrichment analysis was conducted to further investigate these genes. Additionally, single-cell sequencing analysis was employed to explore the relationship between FEN1 expression and functional states. Cox regression analysis was implemented to construct a prognostic model, and a nomogram for prognosis was developed. Our analysis of The Cancer Genome Atlas and Gene Expression Omnibus datasets revealed a significant upregulation of FEN1 in colon cancer. However, while FEN1 expression showed no notable correlation with prognosis, it displayed associations with metastasis. Single-cell sequencing analysis further confirmed a positive correlation between FEN1 expression and colon cancer metastasis. Furthermore, we detected marked discrepancies in drug responsiveness between the High_FEN1 and Low_FEN1 groups, identifying 342 differentially expressed genes. Enrichment analysis showed significant suppression in processes related to DNA replication, spliceosome, and cell cycle pathways in the Low_FEN1 group, while the calcium signaling pathway, cAMP signaling pathway, and other pathways were activated. Of the 197 genes differentially expressed and strongly linked to FEN1 expression, 39 were significantly implicated in colon cancer prognosis. Finally, we constructed a risk signature consisting of 5 genes, which, when combined with drug treatment and pathological staging, significantly improved the prediction of colon cancer prognosis. This study offers novel insights into the interplay among FEN1 expression levels, colon cancer metastatic potential, and sensitivity to therapeutic agents. Furthermore, we successfully developed a multi-gene prognostic risk signature derived from FEN1.

Abstract 6786: Assessment of immune cell infiltration and cancer metastatic potential in Akura™ Immune Flow Chip - A microfluidic 3D spheroid system

Abstract Evaluation of novel therapeutics often fails to reliably predict severe complications in patients, especially when circulating cells are involved. The reasons may include inter-species differences upon using animal models or the lack of relevant in vitro systems. Moreover, existing in vitro systems mostly rely on static investigations of different cell types leading to overestimation of effects due to non-representative cell-tissue interactions. The incorporation of medium flow may facilitate to mimic physiological conditions more closely. To tackle current limitations of perfused organ-on-chip approaches, we developed a microfluidic chip and operation concept, which prevents undesired sedimentation and accumulation of cells in suspensions. The Akura™ Immune Flow platform was designed to study flow-dependent recruitment of circulating cells to different tissue spheroids via gravity-driven perfusion over several days. The Akura™ Immune Flow platform features standardized formats for co-culturing up to seven spheroids with suspended cells in each microfluidic channel. On-chip staining protocols enabled monitoring of the co-culture. The system allowed for application and extractions of cellular components and liquid for further off-chip analysis. Primary tissue and cell line spheroids (liver and tumor) could be retained in the respective chambers and remained viable over six to 14 days. Circulating cells were kept viable and in suspension for up to six days (PBMCs) and14 days (Prostate Cancer (PCa) cells) respectively. PBMCs were not activated by flow-induced shear forces. Unspecific stimulation of T-cells led to physiological expression of early and late activation markers (CD69 and CD25), which were detected by flow cytometry in periodically collected cells. Multi-photon microscopy imaging confirmed that PBMCs interacted with and infiltrated into 3D tumor spheroids. Application of PCa cells to primary liver spheroids, cultured in Akura™ Immune Flow chips allowed for assessment of their invasive potential. Confocal imaging revealed adhesion of cancer cells to the liver spheroids and offers the potential to study the ability of tissue invasion at later time points. The simple design of the chip facilitates user-friendly operation and high-throughput implementation in cancer research and drug testing. The selected applications support the relevance of using flow solutions for physiologically more complex processes. This work constitutes an important step towards device application as a tool for basic research as well as for efficacy studies of immunotherapeutic drug candidates Citation Format: Tamara Häfeli, Silas Riss, Christian Lohasz, Dzhansu Hasanova, Svenja Lützow, Lisa Hölting, Michal Rudnik, Franziska Linke, Wytske M van Weerden, Laure-Anne Ligeon, Andreas Hierlemann, Mario Modena, Olivier Frey. Assessment of immune cell infiltration and cancer metastatic potential in Akura™ Immune Flow Chip - A microfluidic 3D spheroid system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6786.

Abstract 197: The GPR52-MCAM axis as a novel regulatory mechanism of breast cancer cell clustering and metastatic potential

Abstract Background: Breast cancer is the most diagnosed cancer worldwide and is the second leading cause of cancer death among women in the United States. Despite breakthroughs in targeted therapies for breast cancer, the 5-year survival rate for women with metastatic breast cancer is 30%. There is a strong rationale to explore the therapeutic potential of G-protein coupled receptors (GPCRs), which comprise the largest class of proteins successfully targeted by FDA-approved drugs. Importantly, at least one-third of GPCRs are “orphans” and remain largely uncharacterized. One of these orphan GPCRs is GPR52. To date, there is no literature on the role of GPR52 in any cancer type, but we find from publicly available clinical data that low mRNA expression of GPR52 in breast tumors correlates with reduced overall survival (hazard ratio=0.67 [0.53-0.83], logrank P= 0.00035) and that GPR52 mRNA levels tend to be lower in tumor metastases compared to primary tumor (n>80, p=4.45e-17). Therefore, we hypothesize that loss of GPR52 may support breast cancer metastasis. Results: We used CRISPR-Cas9 to knockout (KO) GPR52 in triple-negative breast cancer cell lines MDA-MB-468 and MDA-MB-231, and in the non-cancerous breast epithelial cell line MCF10A, and confirmed the generation of frameshift mutations by Sanger sequencing. Interestingly, we observed that GPR52 KO cells clustered together in vitro in 2D and hypothesized that this characteristic may allow GPR52 KO breast cancer cells to increase their metastatic potential. We conducted invasion assays though Matrigel and found that GPR52 KO cells were more likely to invade as sheets or clusters. To determine the in vivo impact of GPR52 loss, we injected MDA-MB-468 GPR52 KO cells in zebrafish (Danio rerio) two days post-fertilization and observed that GPR52 loss led to increased metastatic foci and total cancer surface area thirty hours post-injection (n≥12, p<0.05). We determined from RNA-sequencing (n=3, p<.0001) and confirmed with western blotting that the melanoma cell adhesion molecule (MCAM) is upregulated in the MCF10A and MDA-MB-468 GPR52 KO cells. Increased mRNA expression of MCAM has been associated with reduced overall survival in breast cancer patients (hazard ratio=1.33 [1.05-1.62], logrank P= 0.02) Conclusion: Knockout of GPR52 from breast cancer cells promotes increased cell clustering in vitro and metastasis in zebrafish. These data support the investigation of GPR52 as a biomarker of cancer aggression and a potential therapeutic target for breast cancer patients whose tumors express GPR52. Citation Format: Sarah Z. Hanif, CheukMan C. Au, Ingrid Torregroza, Bhavneet Bhinder, Lukas Dow, Olivier Elemento, Todd Evans, Kristy A. Brown. The GPR52-MCAM axis as a novel regulatory mechanism of breast cancer cell clustering and metastatic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 197.

Abstract 4158: Non-invasive mapping of acidosis and extracellular lactosis for assessing tumor invasion in vivo

Abstract Tumor cells typically display a hyperglycolytic metabolic phenotype characterized by increased lactate production, known as the Warburg effect. This drift in oxidative metabolism often results in a more acidic microenvironment. This adverse microenvironment represents a unique metabolic signature in cancer cells with more invasive phenotypes. However, to date, there are no effective methods available to evaluate cancer progression and metastatic potential in vivo. To bridge this gap, we have developed a molecular imaging technique (CEST-MRI) that can track extracellular pH (pHe; acidoCEST) and extracellular lactate levels (shiftCEST) simultaneously to discern different cancer phenotypes. In this study we have generated and selected in vivo two PyMT derived murine breast cancer cell lines, a parental and a G6 metastatic. We first characterized the cell’s metabolism by analyzing key biomarkers with qPCR, Western Blot and microscopy, and confirmed their distinct metabolic profiles with Seahorse and RNA Sequencing. Notably, the metastatic PyMT exhibited a more active metabolism, aligning with the invasive phenotype observed by spheroid invasion assay. Herein, we combined the injection of iopamidol and shift reagent (SR) to perform quasi-simultaneous acidoCEST and shiftCEST. First, we assessed the approach in vitro by introducing iopamidol and SR into phantoms containing the individual contrast agents, and the combination in pure water and cells supernatants at different pHe and lactate levels. We performed LDH assays to cross-validate the extracellular concentrations and monitored the pH with a micro pH meter (Mettler-Toledo). In vivo, the cells were injected orthotopically in the 4th mammary fat pad of C57BL/6N mice. Hybrid shift/acidoCEST sequences were optimized and acquired following the injection of the iopamidol+SR solution. Preclinical shift/acidoCEST enabled the simultaneous and accurate determination of extracellular acidosis and lactosis, revealing increased acidification in the metastatic models despite lower lactate secretion. Metastatic tumors exhibited a negative correlation between tumor volume and pHe, indicating the significance of acidity in mutagenesis and invasion. In contrast, no correlation was observed for the parental non-metastatic tumor. Additionally, the metastatic tumors had lower levels of lactate than the parental tumors, which could be attributed to their higher mitochondrial activity, reflecting a diverted metabolic fitness. In summary, our study highlights the efficacy of shift/acidoCEST as a reliable method for non-invasive metabolic imaging, enabling the simultaneous detection of extracellular acidity and lactate production by MRI. This research introduces a unique platform for assessing the metabolic aggressiveness of cancer, emphasizing the significance of acidity and lactate production as crucial biomarkers in cancer invasion. Citation Format: Anais Choffart, Remy Chiaffarelli, Max Zimmermann, Laura Kuebler, André Martins. Non-invasive mapping of acidosis and extracellular lactosis for assessing tumor invasion in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4158.

Abstract 1508: Membrane heparan sulfate proteoglycans work with cadherins to establish the directional orientation of migrating cancer cells

Abstract A role of heparan sulfate proteoglycans (HSPGs) in cancer cell differentiation, proliferation and migration has been recognized and related to their ability to specifically interact with growth factors, morphogens, and extracellular matrix proteins, mainly through sulfated groups on their glycosaminoglycan (GAG) chains. Due to the considerable diversity of HSPGs and of their GAG chains, and to the lack of specific ligands, a precise molecular characterization of the biological role of HSPGs in cancer cells is still lacking. HSPGs, besides working as coreceptors for growth factors and morphogens, may have a determinant and autonomous role in cancer signaling events, regulating cell adhesion, migration, and invasiveness. Being overexpressed and over sulfated in cancer cells, HSPGs may become attractive tumor targets for cancer diagnosis and therapy. We had used the tetra-branched peptide NT4, which binds sulphated GAG chains of HSPGs, to validate HSPGs as potential tumor associated antigens in different human solid tumors. The same NT4 peptide had been tested as a tumor targeting agent for either cancer cell imaging or therapy, in vitro and in vivo [1]. Once identified the sulfated GAG specificity of NT4, the peptide has also been used as a specific tool for studying the role of HSPGs in cancer cell migration and invasiveness, with the aim of proposing HSPG as potential drug targets for interfering with cancer invasiveness and metastatic potential [2,3]. We found that NT4 inhibits adhesion, oriented migration, and colony formation in different human cancer cell lines. We investigated the role of HSPGs in migration of different human cancer cell lines, displaying either single-cell mesenchymal migration (PANC-1 pancreas adenocarcinoma, and MDA-MB-231 breast adenocarcinoma) or collective migration (MCF-7 breast adenocarcinoma). After assessing the expression of HSPG and of E- and N- cadherin in each cell line, their specific cellular distribution was detected by confocal microscopy in migrating cells, in wound healing experiments. We found that distribution of either E- or N- cadherins on the membrane of migrating cells is complementary to that of HSPG. This is particularly clear in collective migration, where HSPGs are exclusively located on the migration front of leader cells, whereas cadherins are only expressed by follower cells. Our results suggest that HSPG may have a crucial role in defining the front of migrating cells, while cadherin-mediated cell-cell contacts on the opposite site, may contribute to inducing protrusion formation at the front of migrating cells, as already suggested [4]. [1]- Brunetti J et al. Sci. Rep. 2015, 5, 17736; [2]- Brunetti J et al. Sci. Rep. 2016, 6, 27174; [3]- Depau L et al. J Med Chem 2020, 63, 15997; [4]- Grimaldi C et al Nat Commun 2020, 11, 5397 Citation Format: Lorenzo Depau, Jlenia Brunetti, Chiara Falciani, Marta Garfì, Maria Francesca Paolocci, Alessandro Pini, Luisa Bracci. Membrane heparan sulfate proteoglycans work with cadherins to establish the directional orientation of migrating cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1508.

Abstract B071: Mesothelial cell motility and contractility promote ovarian cancer metastatic potential through a PKA-dependent mechanism

Abstract Ovarian cancer is the leading cause of death among gynecological cancers, and metastasis to the peritoneum occurs in over 60% of patients. To form these metastatic implants, disseminated cancer cells attach and invade through the mesothelial barrier that lines the peritoneal organs in the abdominal cavity. A better understanding of cancer-mesothelial interactions will lead to identification of mesothelial-specific prognostic markers and the discovery of therapeutic targets to limit ovarian cancer metastatic spread. The goal of our studies is to dissect how mesothelial cell contractility and barrier integrity impact the metastatic potential of high-grade serous ovarian cancer. We developed an imaging-based live cell assay that assesses the rate at which the ovarian cancer spheroids transmigrate across mesothelial monolayers (we termed this process “clearance”) and preconditioned the mesothelial monolayer with different pharmacologic agents. We discovered that treatment with forskolin, a cAMP activator, significantly reduced the number of clearing spheroids compared to the control untreated condition. Inhibition of protein kinase A (PKA) in mesothelial cells that were treated with forskolin reversed the anti-metastatic effects and restored clearance rates to baseline levels. Next, we analyzed mesothelial cell-cell junctions, cytoskeletal organization, traction forces and cell motility patterns. Compared to the control condition, forskolin treated mesothelial cells exhibited higher expression levels of ZO-1 and β-catenin junctions, as well as reduction in actin stress fibers. Consistent with these results, we found that forskolin reduced traction forces and mesothelial cell migration was assessed through a wound healing assay. To evaluate the impact of increasing mesothelial contractility, we treated mesothelial cells with calyculin A, a potent phosphatase inhibitor that elevated expression of phospho-myosin to promote traction forces and increase spheroid clearance rates. Transcriptomic and proteomic studies of mesothelial monolayers treated with forskolin revealed a role for the c-Jun pathway. c-Jun is known to regulate cell migration and response to environmental stress, and thus presents a promising candidate for enhancing mesothelial barrier function and protecting against ovarian cancer spheroid invasion. Our findings suggest that normalizing mesothelial cell contractility via a PKA-dependent mechanism enhances barrier integrity and limits the invasive potential of ovarian cancer spheroids. A better understanding of cancer-mesothelial paracrine signaling and environmental stressors in the peritoneal cavity that lead to mesothelial barrier dysfunction hold promise for the discovery of mesothelial-targeted therapies to reduce ovarian cancer metastatic dissemination. Citation Format: Dorota Jazwinska, Youngbin Cho, Ioannis Zervantonakis. Mesothelial cell motility and contractility promote ovarian cancer metastatic potential through a PKA-dependent mechanism [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B071.

FSP1 is a predictive biomarker of osteosarcoma cells’ susceptibility to ferroptotic cell death and a potential therapeutic target

Human osteosarcoma (OS) is a relatively rare malignancy preferentially affecting long body bones which prognosis is often poor also due to the lack of effective therapies. Clinical management of this cancer basically relies on surgical removal of primary tumor coupled with radio/chemotherapy. Unfortunately, most osteosarcoma cells are resistant to conventional therapy, with the undergoing epithelial-mesenchymal transition (EMT) giving rise to gene expression reprogramming, thus increasing cancer cell invasiveness and metastatic potential. Alternative clinical approaches are thus urgently needed. In this context, the recently described ferroptotic cell death represents an attractive new strategy to efficiently kill cancer cells, since most chemoresistant and mesenchymal-shaped tumors display high susceptibility to pro-ferroptotic compounds. However, cancer cells have also evolved anti-ferroptotic strategies, which somehow sustain their survival upon ferroptosis induction. Indeed, here we show that osteosarcoma cell lines display heterogeneous sensitivity to ferroptosis execution, correlating with the mesenchymal phenotype, which is consistently affected by the expression of the well-known anti-ferroptotic factor ferroptosis suppressor protein 1 (FSP1). Interestingly, inhibiting the activity or expression of FSP1 restores cancer cell sensitivity to ferroptosis. Moreover, we also found that: i) AKRs might also contribute to resistance; ii) NRF2 enhances FSP1 expression upon ferroptosis induction; while iii) p53 contributes to the regulation of FSP1 basal expression in OS cells.In conclusion, FSP1 expression can potentially be used as a valuable predictive marker of OS sensitivity to ferroptosis and as a new potential therapeutic target.

From the Colon to the Liver: How Gut Microbiota May Influence Colorectal Cancer Metastatic Potential.

The gut microbiota's influence on human tumorigenesis is a burning topic in medical research. With the new ontological perspective, which considers the human body and its pathophysiological processes as the result of the interaction between its own eukaryotic cells and prokaryotic microorganisms living in different body niches, great interest has arisen in the role of the gut microbiota on carcinogenesis. Indeed, dysbiosis is currently recognized as a cancer-promoting condition, and multiple molecular mechanisms have been described by which the gut microbiota may drive tumor development, especially colorectal cancer (CRC). Metastatic power is undoubtedly one of the most fearsome features of neoplastic tissues. Therefore, understanding the underlying mechanisms is of utmost importance to improve patients' prognosis. The liver is the most frequent target of CRC metastasis, and new evidence reveals that the gut microbiota may yield an effect on CRC diffusion to the liver, thus defining an intriguing new facet of the so-called "gut-liver axis". In this review, we aim to summarize the most recent data about the microbiota's role in promoting or preventing hepatic metastasis from CRC, highlighting some potential future therapeutic targets.

Enhancing Angioinvasion Assessment in Papillary Thyroid Cancer Via a Biomarker Panel Involving TAC, 8-OHdG, and Sortilin.

Papillary thyroid cancer (PTC) aggressiveness and metastatic potential are closely associated with angioinvasion. Identifying angioinvasion accurately is imperative for treatment planning and prognosis. This study explores serum biomarkers, including 8-hydroxydeoxyguanosine (8-OHdG) and oxidative status markers (total oxidative capacity, total antioxidant capacity [TAC], and sortilin), as potential indicators of angioinvasion in PTC. A cross-sectional study involving 50 angioinvasive patients with PTC (study group) and 30 patients with PTC with low-risk features (reference group). Serum levels of biomarkers were analyzed to determine their association with angioinvasion. Patients were recruited from Department of Endocrinology, Diabetology, and Internal Diseases, Medical University of Bialystok, Poland, ensuring representation from a diverse clinical context. Participants included patients with PTC, with 50 in the study group and 30 in the reference group. Selection criteria, matching characteristics, and participant completion rates were duly recorded. Serum biomarkers were measured to evaluate their association with PTC angioinvasion. Primary outcome measures included serum levels of 8-OHdG, total oxidative capacity, TAC, and sortilin. Serum levels of 8-OHdG and sortilin were significantly elevated in angioinvasive PTC, whereas TAC showed a notable decrease (all P < .01). A regression panel combining TAC, 8-OHdG, and sortilin demonstrated a high area under the curve value (0.963) for angioinvasion discernment. Measuring TAC, 8-OHdG, and sortilin levels may serve as potential biomarkers for identifying angioinvasion in PTC. The combined assessment of these biomarkers enhances angioinvasion discernment, aiding risk stratification and personalized treatment decisions. Further validation studies are required before integrating these biomarkers into routine clinical practice. The study adheres to the provided structure, providing concise and supported conclusions based on the results.

Unraveling the role of C1GALT1 in abnormal glycosylation and colorectal cancer progression.

C1GALT1 plays a pivotal role in colorectal cancer (CRC) development and progression through its involvement in various molecular mechanisms. This enzyme is central to the O-glycosylation process, producing tumor-associated carbohydrate antigens (TACA) like Tn and sTn, which are linked to cancer metastasis and poor prognosis. The interaction between C1GALT1 and core 3 synthase is crucial for the synthesis of core 3 O-glycans, essential for gastrointestinal health and mucosal barrier integrity. Aberrations in this pathway can lead to CRC development. Furthermore, C1GALT1's function is significantly influenced by its molecular chaperone, Cosmc, which is necessary for the proper folding of T-synthase. Dysregulation in this complex interaction contributes to abnormal O-glycan regulation, facilitating cancer progression. Moreover, C1GALT1 affects downstream signaling pathways and cellular behaviors, such as the epithelial-mesenchymal transition (EMT), by modifying O-glycans on key receptors like FGFR2, enhancing cancer cell invasiveness and metastatic potential. Additionally, the enzyme's relationship with MUC1, a mucin protein with abnormal glycosylation in CRC, highlights its role in cancer cell immune evasion and metastasis. Given these insights, targeting C1GALT1 presents a promising therapeutic strategy for CRC, necessitating further research to develop targeted inhibitors or activators. Future efforts should also explore C1GALT1's potential as a biomarker for early diagnosis, prognosis, and treatment response monitoring in CRC, alongside investigating combination therapies to improve patient outcomes.

Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance.

Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer-promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in perinecrotic hemorrhagic tumor regions. These cells resembled antiinflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-Seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial-mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFN-γ and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma-bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance.

RNF185 Control of COL3A1 Expression Limits Prostate Cancer Migration and Metastatic Potential.

RNF185 is identified as an important regulator of prostate cancer migration and metastasis, in part due to its regulation of COL3A1. Both RNF185 and COL3A1 may serve as novel markers for prostate tumors.

Secretory phospholipase (sPLA2-IIA) regulates breast cancer stem cells differentiation and metastatic potential

Breast cancer is the second most cancer worldwide in females. The primary factor responsible for tumor recurrence is the presence of breast cancer stem cells (BCSCs), which escape the chemo-radiotherapy. In this study, we have investigated the role of Secretory phospholipase-A2 Group 2A (sPLA2-IIA) that is overexpressed in BCSCs of MCF7 and MDA-MB-231 breast cancer cell lines. Further, overexpression of sPLA2-IIA revealed an increased EGFR/JNK/c-JUN/c-FOS signaling in BCSCs, while sPLA2-IIA knockdown significantly reduced the percentage of BCSCs and decreased signaling in both the cell lines. Importantly, sPLA2-IIA knockdown showed differentiation of BCSCs. Strikingly, PET imaging showed a decreased metastatic potential of BCSCs. Our study revealed a novel role of sPLA2-IIA in regulating BCSCs, which play a crucial role in regulating the differentiation and metastatic potential of BCSCs.

Activation of NLRP2 in Triple-Negative Breast Cancer sensitizes chemotherapeutic therapy through facilitating hnRNPK function

Nucleotide-binding oligomerization domain (NOD)-like receptor type 2 protein (NLRP2) was reported to inhibit NF-κB in response to inflammatory stimuli, but its role in tumors remains elusive. We screened out NLRP2 from mouse models of breast cancer metastasis. Bioinformatics analysis showed NLRP2 expression was positively correlated with survival rate and negatively correlated with the potential of cancer metastasis. Its significance in Triple-Negative Breast Cancer (TNBC) was investigated by gain- and loss-of-function studies in vivo and vitro. Re-expression of NLRP2 dramatically inhibited the growth and metastasis of the xenograft model of MDA-MB-231 cells. Mechanically, NLRP2 confined hnRNPK within cytoplasm, which in turn blocked vimentin mRNA production. Not only that, NLRP2 further enhanced the H2O2-induced high level of p53&Bax and hence dramatically increased the apoptosis rate (fivefold). Likewise, carboplatin-treated cells showed decreased cell viability, suggesting that patients of TNBC with high level of NLRP2 respond well to chemotherapeutics. Under the stimulus of H2O2, NLRP2–hnRNPK no longer stayed in the cytoplasm, but entered the nucleus to increase the expression of p53 and hence enhanced corresponding apoptosis effect, increasing Bax expression. It suggested that NLRP2 helps p53 enter the nucleus to induce apoptosis. This study revealed a novel function of NLRP2 that modulated oncogenic and anti-oncogenic characteristics of hnRNPK, and provided a new biomarker for TNBC chemotherapy.

Vibration Therapy for Cancer-Related Bone Diseases

Patients undergoing cancer treatments and/or suffering from metastatic bone lesions experience various skeletal-related events (SREs), substantially reducing functional independence and quality of life. Therefore, researchers are working towards developing new interventions by harnessing the bone’s innate anabolic response to mechanical stimulations. Whole body vibration (WBV) has recently gained interest due to its nature of being safe, effective, and easy to perform. In this review, we will summarize the most cutting-edge vibration studies of cancer models and bone-cancer cell interactions. We will also discuss various parameters, including age, vibration settings, and differences between bone sites, which may affect vibration efficacy. Studies have shown that WBV improves bone mineral density (BMD) and bone volume in patients and mice with cancer. WBV also reduces tumor burden and normalizes bone vasculature in mice. At the cellular level, vibration promotes interactions between bone cells and cancer cells, which reduce osteoclastogenesis and inhibit cancer metastatic potential. Hence, WBV could potentially serve as a new intervention or adjuvant treatment to attenuate cancer progression while preserving bone health.