Colorectal Cancer Metastasis Research Articles

Exploring the link between liver cirrhosis and liver metastasis in colorectal cancer.

301 Background: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer mortality in the world. Although it is now associated with improved outcomes due to advancements in treatment modalities, CRC continues to be the most common source of liver metastasis. Previous studies have shown cirrhotic livers to be at reduced risk of metastatic disease. Our study aims to investigate the association between colorectal cancer and liver metastasis in the presence of concomitant liver cirrhosis. Methods: The National Inpatient Sample (NIS) was queried to identify all hospitalizations with colorectal cancer utilizing ICD-10 codes C18.x, C19.x, and C20.x from 2016 to 2020 and were further classified based on the presence or absence of cirrhosis. Demographic and clinical data were analyzed using chi-squared tests, independent sample t-tests, and binary logistic regression (adjusted for age, gender, and Charlson comorbidity index or CCI). The primary outcome studied was liver metastasis. Secondary outcomes were hepatic encephalopathy, portal hypertension, and spontaneous bacterial peritonitis. Statistical significance is indicated by a p-value less than 0.05. Results: A total of 255,599 hospitalizations with colorectal cancer were identified. Out of these, 5,370 (2.1%) had liver cirrhosis and 250,229 (97.9%) did not. Hospitalizations with CRC and concomitant cirrhosis had higher comorbidities as per the Charlson Comorbidity Index (10.5 vs 8.1, p-value<0.001) and higher mortality rates (8.5% vs 4.2%, p-value<0.001). Higher rates of liver metastasis (26.5 vs 23.4, p <0.001) and portal hypertension (26.1% vs 0.3%, p<0.001) were observed in the cirrhosis subgroup. This subgroup also has a significantly higher risk of SBP (2.8% vs 0.2%, p <0.001). Conclusions: This is a large retrospective study analyzing the impact of cirrhosis on liver metastasis in patients with colorectal cancer. Patients with concomitant cirrhosis consistently have increased liver metastasis and worse outcomes. The results of this study imply that diligent CRC screening is of utmost importance in patients with cirrhosis. Patients with CRC and coexisting cirrhosis would benefit from routine surveillance such as carcinoembryonic antigen (CEA) screening or CT scans to allow early detection of liver metastases which could potentially improve outcomes. Colorectal Cancer Patients No Cirrhosis (N=250,229) Cirrhosis (N=5,370) p-value Age (in years) 65.79 ± 13.8 65.04 ± 10.9 <.001 Sex (Female) 47.3% 36.8% <.001 Charlson Comorbidity Index 8.1 ± 3.6 10.5 ± 3.7 <.001 Mortality 4.2% 8.5% <.001 Length of Stay 6.6 ± 7.2 7.4 ± 7.2 <.001 Liver Metastasis 23.4% 26.5% <.001 Hepatic Encephalopathy 0.0% 0.2% <.001 Portal hypertension 0.3% 26.1% <.001 Spontaneous Bacterial Peritonitis (SBP) 0.2% 2.8% <.001

STAT3-related lncRNAs in colorectal cancer progression; Special focus on immune cell's evasion.

Colorectal cancer (CRC) is globally ranked as the third leading cause of cancer-related deaths in both men and women. There is an urgent need for novel biomarkers to facilitate early diagnosis and enhance patient care, thereby improving treatment response and reducing mortality rates. Signal transducer and activator of transcription 3 (STAT3) is essential for controlling the anti-tumor immune response since it is a hub for several oncogenic signaling pathways. In the tumor environment, STAT3 is widely overactivated in both malignant and non-cancerous cells. It is involved in suppressing the expression of critical immune activation regulators and encouraging the synthesis of immunosuppressive substances. Long noncoding RNAs (lncRNAs), a kind of non-coding RNA, are critical for CRC development, apoptosis, and metastasis because they influence important signaling pathways such as STAT3 signaling and contribute to gene regulation at the epigenetic, transcriptional, and post-transcriptional levels. Moreover, lncRNAs have a significant role in modifying the TME and control the expression of important immunological checkpoints, such as PD-L1. Therefore, a comprehensive understanding of the regulatory roles of lncRNAs is crucial for identifying diagnostic, prognostic, and predictive biomarkers for CRC. Thus, the objective of the present review study is to provide a comprehensive overview of the interaction between the STAT3 signaling pathway and various lncRNAs, as well as their implications for apoptosis, metastasis, and immune evasion in CRC.

Spatial transcriptomics and lethality-associated stromal remodeling of colorectal cancer.

227 Background: Colorectal cancer (CRC) is surgically resectable and eminently screenable yet remains a lethal entity with high affinity to metastasise synchronously and metachronously. It has been proposed that cellular and extracellular components of the microenvironment contribute to metastatic potential. Dissociative profiling techniques such as bulk transcriptomic and single-cell RNA sequencing have contributed insight but limited therapeutic progress. Spatial transcriptomic (ST) assessment allows molecular profiling of tissue while preserving tissue architecture. Here we employ ST approaches to interrogate tumor compartments of primary resectable and matched synchronous CRC demonstrating stromal signatures with distinct collagen expression associated with outcome. Methods: 25 patients with primary resectable CRC and 4 patients with matched primary CRC and liver metastasis (CRLM) underwent single-cell spatial transcriptomics using the Nanostring CosMx Spatial Molecular Imager (SMI, 1000plex gene panel) (Discovery cohort). 71681 epithelial and 88806 stromal cells with intact spatial resolution were analysed. The spatial single-cell signatures were reconstituted in 89 patients using the Nanostring GeoMx Digital Spatial Profiler (Validation cohort). 3 GeoMx compartments were analysed: Epithelial (PanCK+); Stroma (aSMA+); Immune (PanCK-aSMA-). Results: CosMx demonstrated 2 distinct collagen signatures: COL1A1,COL1A2,COL3A1 associated with normal fibroblasts; COL9A2 associated with cancer-related stroma and lethal subtypes of epithelial cell. In the GeoMx validation cohort, 42 patients expressed the COL1A1 signature in the aSMA compartment and 47 did not (5 year recurrence free survival: 0.88 vs 0.49, p < 0.005) with different morphological patterns of each distinct aSMA group. In patients with favourable prognosis, chemokine high epithelial subtypes expressed CXCL5 and recruited COL9A2-, IL6+ neutrophils to the surrounding microenvironment. In contrast, epithelial cells in patients with poor prognosis expressed CXCL8 and recruited COL9A2+ neutrophils which were frequently in contact with SPP1+ macrophages. Conclusions: We have used ST approaches to interrogate cellular compartments of CRC demonstrating stromal subtypes that impact outcome. These insights could be used in the clinical setting to quantify COL9A2 expression in aSMA+ cells to prognosticate patients. Targeting of tumor collagen has been proposed to augment existing anti-cancer therapies and this work has demonstrated COL9A2 as a potential target in need of further investigation.

A comprehensive study of clinical and molecular features in patients with metastatic colorectal cancer with and without liver mets.

242 Background: Colorectal cancer (CRC) most frequently metastasizes to the liver, and patients (pts) with liver metastasis (mets) at the time of metastatic diagnosis tend to have poorer outcomes compared to pts with non-liver mets. However, the reason for this discrepancy is not well-defined. We thus aimed to identify any distinct molecular or clinical characteristics that could contribute to the poor outcomes associated with liver mets of CRC. Methods: Pts diagnosed with metastatic CRC from 2014-2022 were identified using the institutional molecular database of CRC. Demographic, clinical, and molecular data were collected by reviewing electronic medical records. Time to next treatment was defined as the time between 1st and 2nd line treatment. We utilized Fisher’s exact tests for categorical variables and both Kaplan-Meier analysis and multivariate Cox proportional hazards models to analyze survival data, with a p-value threshold of <0.05 for statistical significance. Results: We identified a total of 217 pts, including pts with liver mets (N=146) and non-liver mets (N=71) at time of diagnosis. Pts with non-liver mets were more likely to have rectal primary than those pts with liver mets (40% vs. 15%, p=0.0001), indicating a distinct pattern of recurrence. Common driver mutations such as KRAS, BRAF, and TP53 were observed at equal frequencies in the liver and non-liver cohorts. In pts without liver mets, age had a significant effect on OS (p < 0.05, HR 1.1). Pts without liver mets with colon primary had worse OS compared to rectum primary (HR= 0.48, 95% CI: 0.24–0.96, p = 0.038). For pts without liver mets, KRAS was not a predictor of outcomes, while BRAF was associated with poorer OS (p<0.001, HR 7.09, 95%CI: 2.31-21.8). Contrarily, for pts with liver mets, KRAS mutation was significantly associated with worse survival (mOS 40.4 vs 61.7 mos, HR 2.04, 95% CI: 1.26-3.30, p=0.004). BRAF mutations were also associated with worse OS for this cohort (p=0.039 and HR 2.86, 95%CI: 1.06-7.77). Median time to the next treatment was significantly shorter in pts with liver mets (13.6 mos) than in pts with non-liver mets (22.6 mos) (HR 1.82, 95% CI 1.28-2.59; p<0.001). OS was longer for pts with non-liver mets compared to those with liver mets (mOS 52.9 mos vs 46.7 mos) though it did not reach statistical significance, likely due to the small sample size. Conclusions: Liver metastasis of CRC is associated with systemic therapy resistance with a shorter time on treatment, indicating treatment resistance associated with liver mets is not limited to immunotherapy. Given similar molecular characteristics in pts with and without liver mets, treatment resistance may be related to the inherent tumor microenvironment of the liver. In this study, pts with distinct molecular features had poorer outcomes, highlighting the importance of developing targeted therapeutics in this population.

WFDC3 sensitizes colorectal cancer to chemotherapy by regulating ATM/ATR kinase signaling pathway.

Chemoresistance is an ongoing challenge for colorectal cancer (CRC) that significantly compromises the anti-tumor efficacy of current drugs. Identifying effective targets or drugs for overcoming chemoresistance is urgently needed. Our previous study showed that WFDC3 served as a tumor suppressor that hindered CRC metastasis. However, the function of WFDC3 in chemotherapy remains unknown. Here, we found that high WFDC3 expression in CRC patients treated with oxaliplatin was associated with a better prognosis. Concordantly, overexpression of WFDC3 significantly increased sensitivity to oxaliplatin in CRC cells, whereas knocking down WFDC3 led to oxaliplatin resistance. In addition, WFDC3 promoted oxaliplatin-mediated suppression of tumor growth invivo. Subsequently, we found that WFDC3 could enhance oxaliplatin-induced DNA damage through inhibiting ATM/ATR signaling. WFDC3 knockdown showed the opposite effects. Moreover, a combination treatment of oxaliplatin and inhibitors for ATM or ATR partially reversed chemoresistance to oxaliplatin in CRC cells with low WFDC3 expression. Our results demonstrate that WFDC3 is possibly a biomarker for increasing oxaliplatin sensitivity in CRC by modulating ATM/ATR kinase signaling. Thus, a combination of oxaliplatin with an ATM or ATR inhibitor is a potential treatment option for improving CRC outcome.

First-line dual immunotherapy to checkmate metastasic colorectal cancer with high microsatellite instability.

First-line dual immunotherapy to checkmate metastasic colorectal cancer with high microsatellite instability.

Non-enhanced abbreviated MRI as a periodic surveillance protocol for colorectal liver metastases compared with contrast-enhanced CT: a prospective observational study.

Adopting appropriate noninvasive radiological method is crucial for periodic surveillance of liver metastases in colorectal cancer (CRC) patients after surgery, which is closely related to clinical management and prognosis. This study aimed to prospectively enroll stage II-III CRC patients for the surveillance of liver metastases, and compare the diagnostic performance of contrast-enhanced CT (CE-CT) and non-enhanced abbreviated MRI (NE-AMRI) during this process. 587 CRC patients undergoing radical resection of the primary tumor were evaluated by 1 to 3 rounds of surveillance tests, consisting of abdominal CE-CT and contrast-enhanced MRI (CE-MRI) within 7days at 6-month intervals. Subsequently, images of NE-AMRI were extracted from the CE-MRI examination, paired CE-CT and NE-AMRI analysis were performed. The lesion-based detection rates between two protocols were compared and a subgroup analysis was performed in lesions with the size of ≤ 10mm. The patient-based sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and the areas under the curves (AUCs) of CE-CT and NE-AMRI in each round were evaluated. Finally, the relationship between the diagnostic accuracy of two protocols and characteristics of patients was explored. The lesion-based detection rates of NE-AMRI in three rounds were all significantly higher than that of CE-CT (p < 0.001, p < 0.001, p=0.003, respectively). In the subgroup analysis of lesions ≤ 10mm, NE-AMRI also performed better than CE-CT (p < 0.001, p=0.002, p=0.005, respectively). The patient-based sensitivities, specificities, NPVs, PPVs of NE-AMRI were higher than those of CE-CT in three rounds of surveillance. The AUCs for NE-AMRI were all significantly better than that for CE-CT in each round (p=0.015, p=0.045, p=0.009, respectively). Furthermore, patient BMI and fatty liver disease had impacts on the diagnostic accuracy of CE-CT protocol, but not on NE-AMRI protocol. NE-AMRI may be a promising periodic surveillance tool for CRC patients after surgery to increase diagnostic accuracy of liver metastases, developing personalized clinical management and improving prognosis, simultaneously avoiding side-effects associated with ionizing radiation and contrast agents.

Impact of Caudate Lobe Resection on Overall Survival and Liver Disease-Free Survival in Colorectal Liver Metastases: A Pilot Study.

Background/Aims: The objective of this study was to evaluate the impact of the resected caudate lobe on survival, particularly in the context of anatomical resection of liver metastases in colorectal cancers without metastases in the caudate lobe. Materials and Methods: Patient data were extracted from the dataset titled "Preoperative CT and Survival Data for Patients Undergoing Resection of Colorectal Liver Metastases (CRLM)." The analysis specifically concentrated on individuals who underwent complete cau- date lobe resection in the absence of radiological signs of metastasis within the caudate lobe itself. To discern the distinct impact of caudate lobe resection on patient outcomes, propensity score matching (PSM) was applied to control for variations across other relevant clinical parameters. Overall survival (OS) and liver disease-free survival (liver DFS) were calculated using the Kaplan-Meier method, while the log-rank test was used to compare survival outcomes between groups. Results: The analysis revealed that patients who underwent total caudate lobe resection exhibited significantly improved OS rates, both in the complete dataset and following PSM (P < .001, HR: 0.43, 95% CI: 0.26-0.72; P = .024, HR: 0.65, 95% CI: 0.59-0.79, respectively). Additionally, liver DFS outcomes were found to be superior in patients who had caudate lobe resection, in both the full dataset and the propensity-matched cohort (P = .014, HR = 0.46, 95% CI: 0.24-0.85; P = .026, HR = 0.5, 95% CI: 0.37-0.79, respectively). Conclusion: These findings suggest that incorporating total caudate lobe resection into the surgical management of CRLM may offer substantial benefits in terms of both OS and liver-specific disease-free survival.

Crosstalk between GLTSCR1-deficient endothelial cells and tumour cells promotes colorectal cancer development by activating the Notch pathway.

Cancer stem cells (CSCs) typically reside in perivascular niches, but whether endothelial cells of blood vessels influence the stemness of cancer cells remains poorly understood. This study revealed that endothelial cell-specific GLTSCR1 deletion promotes colorectal cancer (CRC) tumorigenesis and metastasis by increasing cancer cell stemness. Mechanistically, knocking down GLTSCR1 induces the transformation of endothelial cells into tip cells by regulating the expression of Neuropilin-1 (NRP1), thereby increasing the direct contact and interaction between endothelial cells and tumour cells. In addition, GLTSCR1 inhibits JAG1 transcription by competing with acetylated p65(Lys-310) to bind to the BRD4 interaction site. Therefore, GLTSCR1 deficiency increases JAG1 expression in endothelial cells. Subsequently, increased JAG1 levels on tip cell membranes bind to Notch on CRC cell membranes, activating the Notch signalling pathway in tumour cells and increasing CRC cell stemness. Taken together, our findings highlight the roles of endothelial cells in CRC development.

ACOX1 activates autophagy via the ROS/mTOR pathway to suppress proliferation and migration of colorectal cancer

Acyl-CoA oxidase 1 (ACOX1), a member of the acyl-coenzyme A oxidase family, is considered a crucial regulator whose dysregulation is implicated in the occurrence and progression of various cancers. This study aims to elucidate the impact of ACOX1 in CRC, shedding light on its potential as a therapeutic target. Through analysis of the GEO dataset, it was found that ACOX1 is significantly downregulated in colorectal cancer (CRC), and this lower expression level is associated with a worse prognosis. Additionally, in vitro as well as in vivo, ACOX1 overexpression dramatically reduced the proliferation and metastasis of CRC cells. Mass spectrometry revealed the crucial role of ACOX1 in fatty acid β-oxidation, as its overexpression led to a substantial increase in reactive oxygen species (ROS) derived from fatty acid β-oxidation. Further experiments demonstrated that ACOX1 overexpression, through modulation of fatty acid metabolism, increased ROS levels, reduced the phosphorylation activation of the key autophagy regulator mTOR, enhanced autophagy, and ultimately suppressed the growth and metastasis of CRC. In conclusions, ACOX1 expression is decreased in CRC. ACOX1 may regulate autophagy by reprogramming lipid metabolism to modulate the ROS/mTOR signaling pathway, consequently inhibiting the proliferation and migration of CRC.

Computational Evaluation of Improved HIPEC Drug Delivery Kinetics via Bevacizumab-Induced Vascular Normalization

Background: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) using the original 30 min protocol has shown limited benefits in patients with peritoneal metastasis of colorectal cancer (PMCRC), likely due to the short duration, which limits drug penetration into tumor nodules. Bevacizumab, an antiangiogenic antibody that modifies the tumor microenvironment, may improve drug delivery during HIPEC. This in silico study evaluates the availability of oxaliplatin within tumor nodules when HIPEC is performed after bevacizumab treatment. Methods: Using a computational fluid dynamics (CFD) model of HIPEC, the temperature and oxaliplatin distribution within the rat abdomen were calculated, followed by a model of drug transport within tumor nodules located at various sites in the peritoneum. The vascular normalization effect of the bevacizumab treatment was incorporated by adjusting the biophysical parameters of the tumor nodules. The effective penetration depth values, including the thermal enhancement ratio of cytotoxicity, were then compared between HIPEC alone and HIPEC combined with the bevacizumab treatment. Results: After bevacizumab treatments at doses of 0.5 mg/kg and 5 mg/kg, the oxaliplatin availability increased by up to 20% and 45% when HIPEC was performed during the vascular normalization phase, with the penetration depth increasing by 1.5-fold and 2.3-fold, respectively. Tumors with lower collagen densities and larger vascular pore sizes showed higher oxaliplatin enhancement after the combined treatment. Bevacizumab also enabled a reduction in the oxaliplatin dose (up to half at 5 mg/kg bevacizumab) while maintaining effective drug levels in the tumor nodules, potentially reducing systemic toxicity. Conclusions: These findings suggest that administering oxaliplatin-based HIPEC during bevacizumab-induced vascular normalization could significantly improve drug penetration and enhance treatment efficacy.

M1A-regulated DIAPH3 promotes the invasiveness of colorectal cancer via stabilization of KRT19

BackgroundIn recent years, the emphasis has shifted to understanding the role of N1-methyladenosine (m1A) in tumor progression as little is known about its regulatory effect on mRNA and its role in the metastasis of colorectal cancer (CRC).MethodsWe performed methylated RNA immunoprecipitation sequencing of tumor tissues and tumor-adjacent normal tissues from three patients with CRC to determine the m1A profile of mRNA in CRC. The expression of diaphanous-related formin 3 (DIAPH3) and its correlation with clinicopathological characteristics of CRC were evaluated using immunohistochemistry and online datasets. The role of DIAPH3 in the migration and invasion of CRC cells was evaluated using wound healing assay, Transwell assay and xenograft metastatic model. The downstream targets of DIAPH3 were screened using mass spectrometry. By co-transfecting DIAPH3 siRNA and a keratin 19 (KRT19) ectopic plasmid into CRC cells, the role of DIAPH3-KRT19 signaling axis was confirmed.ResultsThe mRNA level of DIAPH3 and its m1A modifications increased simultaneously in the CRC tissues. In addition, high DIAPH3 expression in CRC tissues is significantly associated with metastasis and progression to an advanced stage. After the knockdown of DIAPH3, the migration and invasion capabilities of CRC cells suffered a notable decline, which could be rescued by overexpressing KRT19. In addition, the proteasome inhibitor MG132 could block the degradation of KRT19 induced by DIAPH3 silencing.ConclusionsOur study reveals that DIAPH3 mRNA was modified in CRC cells by m1A methylation. Silencing DIAPH3 suppresses the migration and invasion of CRC cells, potentially through the proteasome-dependent degradation of downstream KRT19.

PCDH17 induces colorectal cancer metastasis by destroying the vascular endothelial barrier

Compromised vascular integrity facilitates the cancer cells extravasation and metastasis. However, the mechanisms leading to a disruption in vascular integrity in colorectal cancer (CRC) remain unclear. In this study, PCDH17 expression was higher in the vascular endothelial cells of colon cancer with distant metastasis, and the rates of PCDH17+ endothelial cells (ECs) was associated with the M stage in clinical pathological characteristics analysis and correlated with a poor survival prognosis. The liver and lung metastatic dissemination of MC-38 was significantly decreased in PCDH17–/–mice. The ubiquitination and degradation of VEGFR2 was prevented by the interaction between PCDH17 and the E3 ubiquitin ligase MARCH5, which causing the separation of internalized VE-cadherin, and increased the vascular permeability and metastasis of CRC. These results highlight the importance of PCDH17 in maintaining vascular integrity, which has emphasis for endothelial barrier function in metastatic cancer. PCDH17 has the potential to be a marker for predicting tumor metastasis as well as a viable treatment target for CRC.

Albumin-bilirubin score: a promising predictor of postoperative distant metastasis in patients with colorectal cancer.

The objective of this study was to investigate the prognostic significance of the preoperative serum albumin-bilirubin (ALBI) score in patients with colorectal cancer (CRC). Preoperative ALBI data from 1506 CRC patients were categorized into high-value and low-value groups, and the clinicopathological characteristics of these groups were compared. A Cox proportional hazards regression model was employed to investigate the risk factors associated with distant metastasis. The Kaplan-Meier method and log-rank test were utilized to analyze the relationship between ALBI scores and 5-year distant metastasis-free survival (DMFS). The incidence of distant metastasis in group B (ALBI ≥ -2.4) was significantly higher at 28.81% compared to group A (ALBI < -2.4), which had an incidence of 23.36% (p = 0.018). ALBI score ≥ -2.4 was identified as an independent risk factor for postoperative distant metastasis of CRC (HR = 1.251, 95%CI: 1.021-1.533, p = 0.031). The incidence of 5-year DMFS was significantly lower in the ALBI ≥ -2.4 group compared to that observed in the ALBI < -2.4 group (χ2 = 5.97, p = 0.015, log-rank test). The ALBI score of ≥ -2.4 emerges as an independent risk factor for the occurrence of distant metastases following CRC surgery.

Non-coding RNAs as mediators of epithelial - Mesenchymal transition (EMT) in metastatic colorectal cancers.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating the development of innovative treatment strategies. Recent research has underscored the significant role of non-coding RNAs (ncRNAs) in CRC pathogenesis, offering new avenues for diagnosis and therapy. In this review, we delve into the intricate roles of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in CRC progression, epithelial-mesenchymal transition (EMT), metastasis, and drug resistance. We highlight the interaction of these ncRNAs with and regulation of key signaling pathways, such as Wnt/β-catenin, Notch, JAK-STAT, EGFR, and TGF-β, and the functional relevance of these interactions in CRC progression. Additionally, the review highlights the emerging applications of nanotechnology in enhancing the delivery and efficacy of ncRNA-based therapeutics, which could address existing challenges related to specificity and side effects. Future research directions, including advanced diagnostic tools, targeted therapeutics, strategies to overcome drug resistance, and the integration of personalized medicine approaches are discussed. Integrating nanotechnology with a deeper understanding of CRC biology offers the potential for more effective, targeted, and personalized strategies, though further research is essential to validate these approaches.

Interdependent roles for growth differentiation factor-15 (GDF15) and LIMS1 in regulating cell migration: Implications for colorectal cancer metastasis.

Colorectal cancer (CRC) ranks second in mortality worldwide while metastasis accounts for most CRC-related deaths. Thus, understanding cell migration, a crucial step in metastasis, is imperative for developing new therapies. Growth Differentiation Factor-15 (GDF15), a member of the Transforming Growth Factor β superfamily, is overexpressed in CRC and promotes metastasis with a so far unknown mechanism. LIMS1 is a cell-matrix adhesion prosurvival protein that is also overexpressed in CRC and localized at the tumor invasive front, while bioinformatics analysis shows that both genes exhibit the same expression pattern in metastatic CRC samples. In the present study, treatment of low-aggressiveness HT29 CRC cells with human recombinant GDF15 (hrGDF15) led to increased LIMS1 expression, increased mRNA level of RhoGTPases RAC1 and RHOA but not CDC42, and increased migration. Conversely, GDF15 or LIMS1-siRNA-mediated silencing in invasive HCT116 cells resulted in downregulation of LIMS1 and GDF15 respectively, decreased RAC1, and RHOA as well as reduced cell migration, which were fully restored by hrGDF15 treatment both in GDF15 and LIMS1-siRNA-treated cells. Our findings indicate that GDF15 and LIMS1 have an interdependent role in the migration process which renders them potent targets for the development of novel therapeutic strategies to inhibit metastatic spread.

Uncovering the Regulatory Role of Long Non-Coding RNAs in Colorectal Cancer Progression and Liver Metastasis: Implications for Therapeutic and Diagnostic Targeting

Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, largely due to metastasis, particularly to the liver, and the limited understanding of the molecular mechanisms underlying this process. In this study, we aimed to investigate the role of long non-coding Methods: RNAs (lncRNAs) are key regulatory factors in CRC progression and metastasis to liver tissues. Using high-throughput sequencing and microarray approaches, we analyzed gene expression profiles from two independent lncRNA datasets to identify potential players involved in liver metastasis. Results: Our findings revealed five lncRNAs—PROX1-AS1, SOX9-AS1, LINC01594, LINC01555, and APOA1-AS—previously known for their roles in CRC progression, now identified as being involved in the liver metastatic process. Additionally, 20 other lncRNAs, including VCAN-AS1, SYP-AS1, SMIM2-IT1, NCOA7-AS1, and LINC01449, were also identified as potential contributors to CRC liver metastasis. Notably, two lncRNAs—SATB2-AS1 and LINC01116—emerged as common candidates across both datasets, suggesting their significant role in promoting CRC metastasis to the liver. These two lncRNAs hold promise as molecular targets for therapeutic and diagnostic development. Conclusion: Our study uncovers a novel layer of regulatory mechanisms involving lncRNAs in CRC liver metastasis. These findings advance our understanding of the molecular behaviors that drive CRC progression and offer new avenues for targeted therapeutic strategies and diagnostic tools, particularly for liver metastasis in CRC.

Multiparameter magnetic resonance imaging-based radiomics model for the prediction of rectal cancer metachronous liver metastasis.

The liver, as the main target organ for hematogenous metastasis of colorectal cancer, early and accurate prediction of liver metastasis is crucial for the diagnosis and treatment of patients. Herein, this study aims to investigate the application value of a combined machine learning (ML) based model based on the multiparameter magnetic resonance imaging for prediction of rectal metachronous liver metastasis (MLM). To investigate the efficacy of radiomics based on multiparametric magnetic resonance imaging images of preoperative first diagnosed rectal cancer in predicting MLM from rectal cancer. We retrospectively analyzed 301 patients with rectal cancer confirmed by surgical pathology at Jingzhou Central Hospital from January 2017 to December 2023. All participants were randomly assigned to the training or validation queue in a 7:3 ratio. We first apply generalized linear regression model (GLRM) and random forest model (RFM) algorithm to construct an MLM prediction model in the training queue, and evaluate the discriminative power of the MLM prediction model using area under curve (AUC) and decision curve analysis (DCA). Then, the robustness and generalizability of the MLM prediction model were evaluated based on the internal validation set between the validation queue groups. Among the 301 patients included in the study, 16.28% were ultimately diagnosed with MLM through pathological examination. Multivariate analysis showed that carcinoembryonic antigen, and magnetic resonance imaging radiomics were independent predictors of MLM. Then, the GLRM prediction model was developed with a comprehensive nomogram to achieve satisfactory differentiation. The prediction performance of GLRM in the training and validation queue was 0.765 [95% confidence interval (CI): 0.710-0.820] and 0.767 (95%CI: 0.712-0.822), respectively. Compared with GLRM, RFM achieved superior performance with AUC of 0.919 (95%CI: 0.868-0.970) and 0.901 (95%CI: 0.850-0.952) in the training and validation queue, respectively. The DCA indicated that the predictive ability and net profit of clinical RFM were improved. By combining multiparameter magnetic resonance imaging with the effectiveness and robustness of ML-based predictive models, the proposed clinical RFM can serve as an insight tool for preoperative assessment of MLM risk stratification and provide important information for individual diagnosis and treatment of rectal cancer patients.

LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models.

Colorectal cancer (CRC) remains a leading cause of cancer death due to metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present the first comprehensive analysis of vertical inhibition of the PI3K/AKT pathway in CRC using FDA-approved drugs alpelisib and capivasertib (an AKT inhibitor) in combination with LY2584702 (an S6K inhibitor) in CRC cell lines and mouse- and patient-derived organoids (PDOs). Tissue microarrays from CRC patients confirmed that LIN28B and PI3K/AKT pathway activation correlate with CRC progression. These findings highlight the critical role of the LIN28B-mediated PI3K/AKT pathway in CRC metastasis, the therapeutic potential of targeted inhibition, and the promise of PDOs in precision medicine in metastatic CRC.

Virulence factor discovery identifies associations between the Fic gene family and Fap2+ fusobacteria in colorectal cancer microbiomes.

Fusobacterium is a bacterium associated with colorectal cancer (CRC) tumorigenesis, progression, and metastasis. Fap2 is a fusobacteria-specific outer membrane galactose-binding lectin that mediates Fusobacterium adherence to and invasion of CRC tumors. Advances in omics analyses provide an opportunity to profile and identify microbial genomic features that correlate with the cancer-associated bacterial virulence factor Fap2. Here, we analyze genomes of Fusobacterium colon tumor isolates and find that a family of post-translational modification enzymes containing Fic domains is associated with Fap2 positivity in these strains. We demonstrate that Fic family genes expand with the presence of Fap2 in the fusobacterial pangenome. Through comparative genomic analysis, we find that Fap2+ Fusobacteriota are highly enriched with Fic gene families compared to other cancer-associated and human gut microbiome bacterial taxa. Using a global data set of CRC shotgun metagenomes, we show that fusobacterial Fic and Fap2 genes frequently co-occur in the fecal microbiomes of individuals with late-stage CRC. We further characterize specific Fic gene families harbored by Fap2+ Fusobacterium animalis genomes and detect recombination events and elements of horizontal gene transfer via synteny analysis of Fic gene loci. Exposure of a F. animalis strain to a colon adenocarcinoma cell line increases gene expression of fusobacterial Fic and virulence-associated adhesins. Finally, we demonstrate that Fic proteins are synthesized by F. animalis as Fic peptides are detectable in F. animalis monoculture supernatants. Taken together, our study uncovers Fic genes as potential virulence factors in Fap2+ fusobacterial genomes.IMPORTANCEAccumulating data support that bacterial members of the intra-tumoral microbiota critically influence colorectal cancer progression. Yet, relatively little is known about non-adhesin fusobacterial virulence factors that may influence carcinogenesis. Our genomic analysis and expression assays in fusobacteria identify Fic domain-containing genes, well-studied virulence factors in pathogenic bacteria, as potential fusobacterial virulence features. The Fic family proteins that we find are encoded by fusobacteria and expressed by Fusobacterium animalis merit future investigation to assess their roles in colorectal cancer development and progression.