Clinical impact of panel gene sequencing on therapy of advanced cancers of the digestive system: a retrospective, single center study.

BACKGROUND: Panel gene sequencing is an established diagnostic tool for precision oncology of solid tumors, but its utility for the treatment of cancers of the digestive system in clinical routine is less well documented. METHODS: We retrospectively identified patients with advanced or metastatic gastrointestinal, pancreaticobiliary or hepatic cancers who received panel gene sequencing at a tertiary university hospital from 2015 to 2022. For these cases, we determined the spectrum of genetic alterations, clinicopathological parameters and treatment courses. Assessment of actionability of genetic alterations was based on the OncoKB database, cancer-specific ESMO treatment guidelines, and recommendations of the local molecular tumor board. RESULTS: In total, 155 patients received panel gene sequencing using either the Oncomine Focus (62 cases), Comprehensive (91 cases) or Childhood Cancer Research Assay (2 cases). The mean age of patients was 61 years (range 24-90) and 37% were female. Most patients suffered from either colorectal cancer (53%) or cholangiocellular carcinoma (19%). 327 genetic alterations were discovered in 123 tumor samples, with an average number of 2.1 alterations per tumor. The most frequently altered genes were TP53, KRAS and PIK3CA. Actionable gene alterations were detected in 13.5-56.8% of tumors, according to ESMO guidelines or the OncoKB database, respectively. Thirteen patients were treated with targeted therapies based on identified molecular alterations, with a median progression-free survival of 8.8 months. CONCLUSIONS: Actionable genetic alterations are frequently detected by panel gene sequencing in patients with advanced cancers of the digestive tract, providing clinical benefit in selected cases. However, for the majority of identified actionable alterations, sufficient clinical evidence for targeted treatments is still lacking.

Onset Time and Characteristics of Postprocedural Bleeding after Endoscopic Resection of Colorectal Lesions: A Multicenter Retrospective Study.

INTRODUCTION: Postprocedural bleeding is a major adverse event after endoscopic resection of colorectal lesions, but the optimal surveillance time after endoscopy is unclear. In this study, we determined onset time and characteristics of postprocedural bleeding events. METHODS: We retrospectively screened patients who underwent endoscopic resection of colorectal lesions at three German hospitals between 2010 and 2019 for postprocedural bleeding events using billing codes. Only patients who required re-endoscopy were included for analysis. For identified patients, we collected demographic data, clinical courses, characteristics of colorectal lesions, and procedure-related variables. Factors associated with late-onset bleeding were determined by univariate and multivariate logistic regression analysis. RESULTS: From a total of 6,820 patients with eligible billing codes, we identified 113 cases with postprocedural bleeding after endoscopic mucosal (61.9%) or snare resection (38.1%) that required re-endoscopy. The median size of the culprit lesion was 20 mm (interquartile range 14-30 mm). The median onset time of postprocedural bleeding was day 3 (interquartile range: 1-6.5 days), with 48.7% of events occurring within 48 h. Multivariate logistic regression analysis demonstrates that a continued intake of antiplatelet drugs (OR: 3.98, 95% CI: 0.89-10.12, p = 0.025) and a flat morphology of the colorectal lesion (OR: 2.98, 95% CI: 1.08-8.01, p = 0.031) were associated with an increased risk for late postprocedural bleeding (>48 h), whereas intraprocedural bleeding was associated with a decreased risk (OR: 0.12, 95% CI: 0.04-0.50, p = 0.001). CONCLUSION: Significant postprocedural bleeding can occur up to 18 days after endoscopic resection of colorectal lesions, but was predominantly observed within 48 h. Continued intake of antiplatelet drugs and a flat polyp morphology are associated with risk for late postprocedural bleeding.

WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis.

BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear. METHODS: We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes. RESULTS: Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis. CONCLUSION: Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.

The Roles of Secreted Wnt Ligands in Cancer.

Wnt ligands are secreted signaling proteins that display a wide range of biological effects. They play key roles in stimulating Wnt signaling pathways to facilitate processes such as tissue homeostasis and regeneration. Dysregulation of Wnt signaling is a hallmark of many cancers and genetic alterations in various Wnt signaling components, which result in ligand-independent or ligand-dependent hyperactivation of the pathway that have been identified. Recently, research is focusing on the impact of Wnt signaling on the interaction between tumor cells and their micro-environment. This Wnt-mediated crosstalk can act either in a tumor promoting or suppressing fashion. In this review, we comprehensively outline the function of Wnt ligands in different tumor entities and their impact on key phenotypes, including cancer stemness, drug resistance, metastasis, and immune evasion. Lastly, we elaborate approaches to target Wnt ligands in cancer therapy.

Targeting euchromatic histone lysine methyltransferases sensitizes colorectal cancer to histone deacetylase inhibitors.

Epigenetic dysregulation is an important feature of colorectal cancer (CRC). Combining epigenetic drugs with other antineoplastic agents is a promising treatment strategy for advanced cancers. Here, we exploited the concept of synthetic lethality to identify epigenetic targets that act synergistically with histone deacetylase (HDAC) inhibitors to reduce the growth of CRC. We applied a pooled CRISPR-Cas9 screen using a custom sgRNA library directed against 614 epigenetic regulators and discovered that knockout of the euchromatic histone-lysine N-methyltransferases 1 and 2 (EHMT1/2) strongly enhanced the antiproliferative effect of clinically used HDAC inhibitors. Using tissue microarrays from 1066 CRC samples with different tumor stages, we showed that low EHMT2 protein expression is predominantly found in advanced CRC and associated with poor clinical outcome. Cotargeting of HDAC and EHMT1/2 with specific small molecule inhibitors synergistically reduced proliferation of CRC cell lines. Mechanistically, we used a high-throughput Western blot assay to demonstrate that both inhibitors elicited distinct cellular mechanisms to reduce tumor growth, including cell cycle arrest and modulation of autophagy. On the epigenetic level, the compounds increased H3K9 acetylation and reduced H3K9 dimethylation. Finally, we used a panel of patient-derived CRC organoids to show that HDAC and EHMT1/2 inhibition synergistically reduced tumor viability in advanced models of CRC.

Multi-omics integration identifies a selective vulnerability of colorectal cancer subtypes to YM155.

Tumor heterogeneity is a major challenge to the treatment of colorectal cancer (CRC). Recently, a transcriptome-based classification was developed, segregating CRC into four consensus molecular subtypes (CMS) with distinct biological and clinical characteristics. Here, we applied the CMS classification on CRC cell lines to identify novel subtype-specific drug vulnerabilities. We combined publicly available transcriptome data from multiple resources to assign 157 CRC cell lines to CMS. By integrating results from large-scale drug screens, we discovered that the CMS1 subtype is highly vulnerable to the BIRC5 suppressor YM155. We confirmed our results using an independent panel of CRC cell lines and demonstrated a 100-fold higher sensitivity of CMS1. This vulnerability was specific to YM155 and not observed for commonly used chemotherapeutic agents. In CMS1 CRC, low concentrations of YM155 induced apoptosis and expression signatures associated with ER stress-mediated apoptosis signaling. Using a genome-wide CRISPR/Cas9 screen, we further discovered a novel role of genes involved in LDL-receptor trafficking as modulators of YM155 sensitivity in the CRC cell line HCT116. Our work shows that combining drug response data with CMS classification in cell lines can reveal selective vulnerabilities and proposes YM155 as a novel subtype-specific drug.

[Prevention of gastrointestinal cancer]. / Prävention gastrointestinaler Tumore.

Throughout the past decades, considerable progress has been made in the (early) diagnosis and treatment of gastrointestinal cancers. However, the prognosis for advanced stages of gastrointestinal tumors remains limited for many patients and approximately one third of all tumor patients die as a result of gastrointestinal tumors. The prevention and early detection of gastrointestinal tumors is therefore of great importance.For this reason, we summarize the current state of knowledge and recommendations for the primary, secondary and tertiary prevention of esophageal, stomach, pancreas, liver and colorectal cancer in the following.

CRISPR/Cas9 for cancer research and therapy.

CRISPR/Cas9 has become a powerful method for making changes to the genome of many organisms. First discovered in bacteria as part of an adaptive immune system, CRISPR/Cas9 and modified versions have found a widespread use to engineer genomes and to activate or to repress the expression of genes. As such, CRISPR/Cas9 promises to accelerate cancer research by providing an efficient technology to dissect mechanisms of tumorigenesis, identify targets for drug development, and possibly arm cells for cell-based therapies. Here, we review current applications of the CRISPR/Cas9 technology for cancer research and therapy. We describe novel Cas9 variants and how they are used in functional genomics to discover novel cancer-specific vulnerabilities. Furthermore, we highlight the impact of CRISPR/Cas9 in generating organoid and mouse models of cancer. Finally, we provide an overview of the first clinical trials that apply CRISPR/Cas9 as a therapeutic approach against cancer.

Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure.

In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy, and these drugs have already become essential for the treatment of various noncurable tumors. However, monotherapy in advanced hepatocellular carcinoma (aHCC) failed to show statistically significant improvement.Recently, the combination of atezolizumab and bevacizumab demonstrated efficacy of combining ICI and VEGF inhibition, further substantiating previous data on synergistic mechanisms among respective substance classes.As TKI treatment is currently standard of care for aHCC, and ICIs are approved by the FDA and available in many areas of the world, numerous patients may have been treated with monotherapy of those drugs. However, it remains unclear if failure to monotherapy has an impact on combination therapy. We therefore report a patient well responding to combination therapy despite previous failures to TKI and ICI monotherapy.

A multicenter open-label phase II trial to evaluate nivolumab and ipilimumab for 2nd line therapy in elderly patients with advanced esophageal squamous cell cancer (RAMONA).

BACKGROUND: Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients. The impact of 2nd line chemotherapy is poorly defined. Recent data demonstrated effectiveness of checkpoint inhibitors in different squamous cell carcinomas. Therefore, we assess combined nivolumab/ipilimumab as 2nd line therapy in elderly ESCC patients. METHODS: RAMONA is a multicenter open-label phase II trial. The primary objective is to demonstrate a significant survival benefit of nivolumab/ipilimumab in advanced ESCC compared to historical data of standard chemotherapy. Primary endpoint is therefore overall survival (OS). Major secondary objective is the evaluation of tolerability. Time to QoL deterioration will thus be determined as key secondary endpoint. Further secondary endpoints are tumor response, PFS and safety. We aim to recruit a total of n = 75 subjects that have to be > 65 years old. Eligibility is determined by the geriatric status (G8 screening and Deficit Accumulation Frailty Index (DAFI)). A safety assessment will be performed after a 3 cycle run-in phase of nivolumab (240 mg Q2W) to justify escalation for eligible patients to combined nivolumab (240 mg Q2W) and ipilimumab (1 mg/kg Q6W), while the other patients will remain on nivolumab only. RAMONA also includes translational research sub-studies to identify predictive biomarkers, including PD-1 and PD-L1 evaluation at different time points, establishment of organoid cultures and microbiome analyses for response prediction. DISCUSSION: The RAMONA trial aims to implement checkpoint inhibitors for elderly patients with advanced ESCC as second line therapy. Novel biomarkers for checkpoint-inhibitor response are analyzed in extensive translational sub-studies. TRIAL REGISTRATION: EudraCT Number: 2017-002056-86 ; NCT03416244 , registered: 31.1.2018.

Pharmacological treatment of hepatocellular carcinoma with cavoatrial tumor thrombus - case series and literature review.

Hepatocellular carcinomas (HCC) that extend into the vena cava and the right atrium have a poor prognosis. Surgical approaches including partial hepatectomy and thrombectomy are the most frequently reported treatment options. However, most patients with advanced HCC are not eligible for complex surgical interventions due to reduced liver function, comorbidities, and metastases. At the same time, systemic treatment options of HCC have expanded in recent years. Here, we report 3 cases of patients with advanced HCC who developed a cavoatrial tumor thrombus (CATT) after initial surgical or interventional therapy. The patients were consequently treated with sorafenib or nivolumab. In all cases, the tumor responded to systemic treatment with disease stabilization or partial regression. Overall survival after diagnosis of CATT was 3 and 17 months for sorafenib and 7 + months for nivolumab. Compared to survival rates of alternative treatment options, systemic therapies demonstrated comparable outcomes. In summary, pharmacotherapy is an efficient and well worth option to treat patients with HCC and CATT and should be an integral part of a multimodal therapy concept.

The effect of gender-specific invitation letters on utilization of colorectal cancer screening.

BACKGROUND AND AIM: Colorectal cancer (CRC) screening can effectively reduce cancer-associated mortality. In Germany, individuals over the age of 50 or 55 have access to CRC screening services. However, utilization rates are persistently low, particular in the male population. This observational study investigates the effect of standard versus gender-specific invitation letters on utilization of CRC screening services. METHODS: We analyzed utilization rates of individuals who were insured by a large health insurance fund in Bavaria, Germany. Persons who became eligible for CRC screening received a standard (2013-2014) or a gender-specific invitation letter (2015-2016). We compared utilization rates within 6 months after receipt of the invitation letter using billing codes of the health insurance fund. RESULTS: Invitation letters were sent to 49 535 individuals, of which 48.8 % were gender-specific. The overall utilization rate did not differ between recipients of the standard versus gender-specific invitation letter (11.6 % vs 11.1 %; RR: 0.97 [0.92-1.02], p = 0.19). However, uptake of screening colonoscopy was significantly higher among recipients of gender-specific invitations (2.9 % vs 3.5 %; RR: 1.21 [1.04-1.39], p = 0.01), whereas utilization of fecal occult blood tests declined (10.4 % vs 9.7 %; RR: 0.93 [0.88-0.99], p = 0.016). CONCLUSIONS: Gender-specific design of invitation letters can modify the patients' preference for specific CRC screening services and increase the acceptance of screening colonoscopy.

Towards a compendium of essential genes - From model organisms to synthetic lethality in cancer cells.

Essential genes are defined by their requirement to sustain life in cells or whole organisms. The systematic identification of essential gene sets not only allows insights into the fundamental building blocks of life, but may also provide novel therapeutic targets in oncology. The discovery of essential genes has been tightly linked to the development and deployment of various screening technologies. Here, we describe how gene essentiality was addressed in different eukaryotic model organisms, covering a range of organisms from yeast to mouse. We describe how increasing knowledge of evolutionarily divergent genomes facilitate identification of gene essentiality across species. Finally, the impact of gene essentiality and synthetic lethality on cancer research and the clinical translation of screening results are highlighted.

caRpools: an R package for exploratory data analysis and documentation of pooled CRISPR/Cas9 screens.

MOTIVATION: Genetic screens by CRISPR/Cas9-mediated genome engineering have become a powerful tool for functional genomics. However, there is currently a lack of end-to-end software pipelines to analyze CRISPR/Cas9 screens based on next generation sequencing. RESULTS: The CRISPR-AnalyzeR for pooled screens (caRpools) is an R package for exploratory data analysis that provides a complete workflow to analyze CRISPR/Cas9 screens. To further support the analysis of large-scale screens, caRpools integrates screening documentation and generation of standardized analysis reports. AVAILABILITY AND IMPLEMENTATION: caRpools, manuals and an open virtual appliance are available at http://github.com/boutroslab/caRpools.

Multiple behavioral factors are associated with occurrence of large, flat colorectal polyps.

PURPOSE: The prevalence of advanced dysplasia and synchronous lesions is particularly high in patients with large, flat colorectal polyps. However, the impact of lifestyle on the development of such polyps is poorly investigated. Hence, this study aims to identify associations between behavioral factors and the occurrence of large, flat colorectal polyps. METHODS: Behavioral factors were retrospectively analyzed in patients with large, flat polyps and control patients with at most one diminutive polyp. Information on lifestyle factors, comorbidities, and demographic parameters were determined by a structured, self-administered questionnaire. RESULTS: Questionnaires of 350 patients with large, flat polyps and 489 control patients were included in the analysis. Most large, flat colorectal polyps contained adenoma with low-grade neoplasia and were located in the right colon. Multivariate analysis showed that advanced age (per 1-year increase-OR 1.09, CI 1.07-1.11, p < 0.0001), frequent cigarette smoking (OR 2.04, CI 1.25-3.32, p = 0.0041), daily consumption of red meat (OR 3.61, CI 1.00-12.96, p = 0.0492), and frequent bowel movements (OR 1.62, CI 1.13-2.33, p = 0.0093) were independent risk factors for occurrence of large, flat colorectal polyps. In contrast, frequent intake of cereals (OR 0.62, CI 0.44-0.88, p = 0.0074) was associated with a reduced risk. CONCLUSION: Multiple behavioral factors modulate the risk for developing large, flat colorectal polyps. This knowledge can be used to improve prevention of colorectal cancer.

Invitation letters increase participation in colorectal cancer screening - results from an observational study.

Background and Aim Participation rates in the German colorectal cancer screening program are low. Starting in 2013, a large health insurance plan in Bavaria, Germany, is sending an additional invitation letter to insured individuals when they turn 50 or 55 years and become eligible for participation in the program. The letter provides detailed information on colorectal cancer screening. We assessed the impact of the invitation letter on utilization rates. Methods Insurance claims data of a total of 48 343 individuals who had turned 50 or 55 years between 2012 to 2014 were reviewed for utilization rates of screening colonoscopy and fecal blood tests. Utilization rates 1 year prior (2012) and 2 years after introduction of the invitation letter (2013 and 2014) were compared. Furthermore, providers of colorectal cancer screening were determined. Results Within 6 months after turning 50 or 55 years, 8.8 - 10.2 % of all insured individuals participated in colorectal cancer screening, with the majority being females. After the introduction of the invitation letter, a moderate increase in participation rates could be observed (increase to 109 % [RR 101.7 - 117.3 %, p = 0.02] in 2014). The uptake rate of screening colonoscopy was significantly higher in recipients of the letter (increase to 138.4 % [RR 110.4 - 173.8 %, p = 0.0043] in 2013 and to 149 % [RR 119.5 - 186.3 %, p = 0.0003] in 2014). Furthermore, a significantly higher proportion of general practitioners and gastroenterologists provided colorectal cancer screening in individuals receiving the invitation letter. Conclusions Introduction of an invitation letter can improve participation rates for colorectal cancer screening.

Risk Factors for Local Recurrence of Large, Flat Colorectal Polyps after Endoscopic Mucosal Resection.

AIMS: Removal of large, flat colorectal polyps by endoscopic mucosal resection (EMR) is effective, but local recurrences occur regularly. This study investigated risk factors for local recurrence. METHOD: Cases of EMR of flat colorectal polyps ≥20 mm at an academic center from 2004 to 2011 were retrospectively analyzed for polyp features, resection technique, complications and local recurrences. Behavioral risk factors were retrospectively determined by self-administered questionnaires. RESULTS: Data were collected for 129 patients (57.3% male, mean age at time of EMR: 65.0 years). Mean polyp size was 37.2 mm. Polyps were mostly adenoma with low-grade dysplasia (58.1%) and predominantly located in the right colon (62%). En bloc resection was performed in 31.8%. The median follow-up time was 40 months. Local recurrence occurred in 26.3% of patients, with 87% being recurrence-free after 1 year (95% CI 81-93%). A history of smoking was reported by 51.6% of patients and 88.4% reported regular alcohol consumption. Univariate analysis showed that polyp size and piecemeal resection were associated with risk of local recurrence. In multivariate analysis, only polyp size was predictive for local recurrence. No association was found for behavioral risk factors. CONCLUSION: Polyp size is the main predictor of local recurrence after EMR of large, flat colorectal polyps.

Outcome of Colorectal Cancer Patients Treated with Combination Bevacizumab Therapy: A Pooled Retrospective Analysis of Three European Cohorts from the Angiopredict Initiative.

BACKGROUND/AIMS: This study is aimed at analyzing the survival rates and prognostic factors of stage IV colorectal cancer patients from 3 European cohorts undergoing combination chemotherapy with bevacizumab. METHODS: Progression free-survival (PFS) and overall survival (OS) were analyzed in 172 patients using the Kaplan-Meier method and uni- and multivariable Cox proportional hazards regression models. RESULTS: The median PFS was 9.7 and the median OS 27.4 months. Patients treated at centers in Germany (n = 97), Ireland (n = 32), and The Netherlands (n = 43) showed a median PFS of 9.9, 9.2, and 9.7 months, OS of 34.0, 20.5, and 25.1 months, respectively. Patients >65 years had a significantly shorter PFS (9.5 vs. 9.8 months) but not OS (27.4 vs. 27.5 months) than younger patients. High tumor grade (G3/4) was associated with a shorter PFS, T4 classification with both shorter PFS and OS. Fluoropyrimidine (FP) chemotherapy backbones (doublets and single) had comparable outcomes, while patients not receiving FP backbones had a shorter PFS. In multivariable analysis, age and non-FP backbone were associated with inferior PFS, T4 classification and therapy line >2nd were significantly associated with poor PFS and OS. CONCLUSION: The observed survival rates confirm previous studies and demonstrate reproducible benefits of combination bevacizumab regimens. Classification T4, non-FP chemotherapy backbone, and age >65 were associated with inferior outcome.

Frequent co-occurrence of high-grade dysplasia in large flat colonic polyps (>20 mm) and synchronous polyps.

BACKGROUND: Large colonic polyps are associated with advanced dysplasia, but prevalence and characteristics of synchronous polyps in patients with large flat colonic polyps are poorly investigated. This study aims to characterize clinicopathological features of large flat colonic polyps and their impact on occurrence and characteristics of synchronous polyps. METHODS: A total of 802 patients that underwent endoscopic mucosal resection (EMR) of flat colonic polyps >20 mm from 2003 to 2014 in an academic endoscopy unit were retrospectively analyzed for size, location and histology of large polyps and synchronous polyps. RESULTS: Average size of large polyps was 34.1 mm (range 20-150 mm, standard deviation 16.1 mm). Histology included 52.5 % adenomas with low-grade dysplasia (LGD), 26.7 % with high-grade dysplasia (HGD), 9.6 % serrated polyps and 11.2 % adenocarcinomas. The majority of large polyps were localized in the proximal colon (61 %). 72.2 % of adenocarcinomas were found in the distal colon, while 80.5 % of all serrated polyps were detected in the proximal colon. Increase in polyp size, advanced age and location in the distal colon were associated with presence of HGD/adenocarcinoma in large polyps, as identified by multivariate analysis. Synchronous polyps were detected in 67.2 % of patients undergoing complete colonoscopy during EMR. Presence of HGD/adenocarcinoma in the large polyp, localization of any synchronous polyp in the rectosigmoid colon and occurrence of multiple synchronous polyps were associated with presence of HGD/adenocarcinoma in synchronous polyps. CONCLUSIONS: Synchronous polyps are frequently found in patients with large flat colonic polyps. The prevalence of synchronous polyps with high grade dysplasia is highest in patients with large flat polyps containing HGD/adenocarcinoma.

Nuclear pore protein POM121 regulates subcellular localization and transcriptional activity of PPARγ.

Manipulation of the subcellular localization of transcription factors by preventing their shuttling via the nuclear pore complex (NPC) emerges as a novel therapeutic strategy against cancer. One transmembrane component of the NPC is POM121, encoded by a tandem gene locus POM121A/C on chromosome 7. Overexpression of POM121 is associated with metabolic diseases (e.g., diabetes) and unfavorable clinical outcome in patients with colorectal cancer (CRC). Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor with anti-diabetic and anti-tumoral efficacy. It is inhibited by export from the nucleus to the cytosol via the RAS-RAF-MEK1/2-ERK1/2 signaling pathway, a major oncogenic driver of CRC. We therefore hypothesized that POM121 participates in the transport of PPARγ across the NPC to regulate its transcriptional activity on genes involved in metabolic and tumor control. We found that POM121A/C mRNA was enriched and POM121 protein co-expressed with PPARγ in tissues from CRC patients conferring poor prognosis. Its interactome was predicted to include proteins responsible for tumor metabolism and immunity, and in-silico modeling provided insights into potential 3D structures of POM121. A peptide region downstream of the nuclear localization sequence (NLS) of POM121 was identified as a cytoplasmic interactor of PPARγ. POM121 positivity correlated with the cytoplasmic localization of PPARγ in patients with KRAS mutant CRC. In contrast, POM121A/C silencing by CRISPR/Cas9 sgRNA or siRNA enforced nuclear accumulation of PPARγ and activated PPARγ target genes promoting lipid metabolism and cell cycle arrest resulting in reduced proliferation of human CRC cells. Our data suggest the POM121-PPARγ axis as a potential drugable target in CRC.