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Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer. Chemoresistance is one of the main challenges for cancer therapy success. Here, the authors show that dual-specificity phosphatase 16 (DUSP16) expression is associated with chemoresistance in several types of cancer through impairing mitochondria-associated apoptosis.

Master splicing regulatorMBNL1 shapes large transcriptomic changes that drive cellular differentiation during development. Here we demonstrate that MBNL1 is a suppressor of tumor dedifferentiation. We surveyed MBNL1 expression in matched tumor/normal pairs across The Cancer Genome Atlas and found that MBNL1 was down-regulated in several common cancers. Down-regulation of MBNL1 predicted poor overall survival in breast, lung, and stomach adenocarcinomas and increased relapse and distant metastasis in triple-negative breast cancer. Down-regulation of MBNL1 led to increased tumorigenic and stem/progenitor-like properties in vitro and in vivo. A discrete set of alternative splicing events (ASEs) are shared between MBNL1-low cancers and embryonic stem cells including a MAP2K7Δexon2 splice variant that leads to increased stem/progenitor-like properties via JNK activation. Accordingly, JNK inhibition is capable of reversing MAP2K7Δexon2-driven tumor dedifferentiation in MBNL1-low cancer cells. Our work elucidates an alternativesplicingmechanism that drives tumor dedifferentiation and identifies biomarkers that predict enhanced susceptibility to JNK inhibition.

Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here, we report that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch of the cholesterol biosynthesis pathway. FAXDC2, a paralog of MSMO1, regulated the abundance of the specific C4-methyl sterols lophenol and dihydro-T-MAS. Highlighting its clinical relevance, FAXDC2 was repressed in Wnt/β-catenin-high cancer xenografts, in a mouse genetic model of Wnt activation, and in human colorectal cancers. Moreover, in primary human colorectal cancers, the sterol lophenol, regulated by FAXDC2, accumulated in the cancerous tissues and not in adjacent normal tissues. FAXDC2 linked Wnts to RTK/MAPK signaling. Wnt inhibition drove increased recycling of RTKs and activation of the MAPK pathway, and this required FAXDC2. Blocking Wnt signaling in Wnt-high cancers caused both differentiation and senescence; and this was prevented by knockout of FAXDC2. Our data show the integration of 3 ancient pathways, Wnts, cholesterol synthesis, and RTK/MAPK signaling, in cellular proliferation and differentiation.

Tumor-specific antibody drugs can serve as cancer therapy with minimal side effects. A humanized antibody, PRL3-zumab, specifically binds to an intracellular oncogenic phosphatase PRL3, which is frequently expressed in several cancers. Here we show that PRL3-zumab specifically inhibits PRL3 + cancer cells in vivo, but not in vitro. PRL3 antigens are detected on the cell surface and outer exosomal membranes, implying an ‘inside-out’ externalization of PRL3. PRL3-zumab binds to surface PRL3 in a manner consistent with that in classical antibody-dependent cell-mediated cytotoxicity or antibody-dependent cellular phagocytosis tumor elimination pathways, as PRL3-zumab requires an intact Fc region and host FcγII/III receptor engagement to recruit B cells, NK cells and macrophages to PRL3 + tumor microenvironments. PRL3 is overexpressed in 80.6% of 151 fresh-frozen tumor samples across 11 common cancers examined, but not in patient-matched normal tissues, thereby implicating PRL3 as a tumor-associated antigen. Targeting externalized PRL3 antigens with PRL3-zumab may represent a feasible approach for anti-tumor immunotherapy. Phosphatase of regenerating liver 3 (PRL3) is usually found intracellularly, and is over-expressed in cancer cells. Here the authors show that PRL-3 is also detectable on cell surface, and can be recognized by PRL3-zumab to recruit immune cells into tumor to promote anti-tumor immunity, thereby implicating PRL-3 as a potential tumor antigen.

Drug resistance and distant metastases are leading causes of mortality in colorectal cancer (CRC), yet the molecular mechanisms linking these processes remain elusive. In this study, we demonstrate that acquired resistance to oxaliplatin, a first-line chemotherapeutic in CRC, enhances metastatic potential through transcriptional reprogramming. Using a clinically relevant dosing regimen, we generated oxaliplatin-resistant CRC cells that displayed increased metastatic potential. Integrated transcriptomic and phenotypic analyses revealed that dysregulated cholesterol biogenesis amplifies TGF-β signaling, which in turn drives expression of SERPINE1 , which serves as a key effector of both oxaliplatin resistance and metastasis. Furthermore, we uncovered a SERPINE1 -associated nine-gene expression signature, RESIST-M, that robustly predicts overall and relapse-free survival across distinct patient cohorts. Notably, RESIST-M stratifies a high-risk subtype of CMS4/iCMS3-fibrotic patients that display the poorest prognosis, underscoring its clinical relevance. Targeting of SERPINE1 or cholesterol biosynthesis re-sensitized resistant, pro-metastatic cells to oxaliplatin in mouse xenograft models. Altogether, this study uncovers a mechanistic link between metabolic rewiring and transcriptional plasticity underlying therapy-induced metastasis in primary CRC. Additionally, it also reveals actionable vulnerabilities that offer both prognostic value and therapeutic potential.

Colorectal cancer (CRC) incidence and mortality in those aged 50 years and above have decreased over the past 2 decades. However, there is a rising incidence of CRC among individuals under 50 years of age, termed early-onset colorectal cancer (EOCRC). Patients with EOCRC are diagnosed at an advanced stage and may be in more psychosocial, emotional, and financial distress. Our study examined the epidemiological shifts in CRC in Singapore, a multiethnic country. CRCs diagnosed at age 20 years and above were identified from the Singapore Cancer Registry (SCR) from 1968 to 2019. Patient characteristics included gender, ethnicity, and age of CRC diagnosis. Population information was obtained from the Department of Statistics Singapore (SingStat). Age-specific incidence rates (ASRs) and age-standardized incidence rates (ASIRs) were calculated. The cohort was divided into 3 age groups: 20-49, 50-64, and ≥65 years. Temporal trends in incidence rates were modeled with joinpoint regression. Birth cohort models were fitted using the National Cancer Institute (NCI) age-period-cohort analysis tool. Cancer-specific survival analysis was performed with the Cox proportional hazards model. In total, 53,044 CRCs were included, and 6183 (11.7%) adults aged 20-49 years were diagnosed with EOCRC. The ASR of EOCRC rose from 5 per 100,000 population in 1968 to 9 per 100,000 population in 1996 at 2.1% annually and rose to 10 per 100,000 population in 2019 at 0.64% annually. The ASR for CRC among adults aged 50-64 years rose at 3% annually from 1968 to 1987 and plateaued from 1987, while the ASR for adults aged 65 years and above rose at 4.1% annually from 1968 to 1989 and 1.3% annually from 1989 to 2003 but decreased from 2003 onwards at 1% annually. The ASR of early-onset rectal cancer increased significantly at 1.5% annually. There was a continued rise in the ASR of EOCRC among males (annual percentage change [APC] 1.5%) compared to females (APC 0.41%). Compared to the 1950-1954 reference birth cohort, the 1970-1984 birth cohort had a significantly higher incidence rate ratio (IRR) of 1.17-1.36 for rectal cancer, while there was no significant change for colon cancer in later cohorts. There were differences in CRC trends across the 3 ethnic groups: Malays had a rapid and persistent rise in the ASR of CRC across all age groups (APC 1.4%-3%), while among young Chinese, only the ASR of rectal cancer was increasing (APC 1.5%). Patients with EOCRC had better survival compared to patients diagnosed at 65 years and above (hazard ratio [HR] 0.73, 95% CI 0.67-0.79, P<.001) after adjusting for covariates. The rise in the incidence of rectal cancer among young adults, especially among Chinese and Malays, in Singapore highlights the need for further research to diagnose CRC earlier and reduce cancer-related morbidity and mortality.

Background At present, there is no consensus on which genotyping platform should serve as the standard for clinical polygenic risk score (PRS) implementation. Previous studies have compared the overall performance and concordance of different genotyping and sequencing technologies; however, these analyses have generally averaged the results over the whole genome. We evaluated differences in a 313-variant breast cancer PRS (PRS 313 ) across genomic platforms and their impact on risk stratification. Methods We compare PRS 313 derived from genotyping arrays (Global Screening Array [GSA], OncoArray-500K [OncoArray], Global Diversity Array [GDA], custom Axiom_PrecipV1 array [ThermoFisher]) and low-coverage genome sequencing (lc-WGS) in 2 cell lines and 92 individuals. Probes are designed for all variants on ThermoFisher (success rate: 259/313). Sanger sequencing profiles indels. Concordance of high-risk classification (PRS 313 scoresum > 0.6) across platforms is assessed using Kappa statistics. Results In saliva samples, indel concordance with Sanger sequencing varies widely (Kappa: 0.007-1.000). PRS 313 -ThermoFisher is predictable from other platforms using linear models, despite systematic differences. Greater agreement is observed between arrays with high imputation overlap (e.g., GDA ~ GSA slope=0.986). Agreement in high-risk classification before mean correction is moderate (Fleiss’s Kappa=0.552) and improves after mean correction (Kappa=0.650). Arrays with similar designs show higher agreement before mean correction (Kappa=0.745). Mean correction narrows high-risk proportions from 4-45% to 15-21%. Overall, 26 of 92 samples are classified as high risk on at least one platform, but only 7 are high risk across all. When restricting to identical variants across all platforms for PRS 313 calculation, the corresponding number of high-risk individuals are 24 and 11. Conclusion Our findings demonstrate that platform-specific variability can influence PRS 313 estimates to potentially reclassify individuals around clinically relevant thresholds. Plain Language Summary This study looks at how different DNA sequencing methods can affect estimates of genetic risk for breast cancer. DNA sequencing is a process that determines the exact order of the building blocks (nucleotides) in a person’s genes. Different sequencing technologies and platforms may read this information slightly differently, leading to variations in the data even when analyzing the same individual. These differences can be important because they might change a person’s estimated risk for breast cancer, especially if the risk score is close to a level where doctors would take action. To study this, we analyzed a previously validated breast cancer risk model based on 313 genetic variants, called a polygenic risk score (PRS). A PRS combines the effects of many small genetic differences across the genome to estimate a person’s overall risk for developing a disease, rather than focusing on a single high-risk gene. We found that the estimated risk could shift depending on the sequencing platform used, revealing systematic biases in how people are classified into risk groups. We also identified concerns with certain types of genetic changes, called insertions and deletions (indels), which are sometimes inconsistently detected across platforms and could affect the reliability of the risk score. Ho et al. investigate the impact of choice of sequencing platform on identification of specific variants for breast cancer risk stratification. Platform-specific variability is found to influence PRS313 estimates, potentially reclassifying individuals around clinically relevant thresholds.

Abstract Background Growing evidence suggests a role for cancer susceptibility genes such as BRCA2 and PALB2 in young-onset colorectal cancers. Using a cohort of young colorectal cancer patients, we sought to identify and provide functional evidence for germline pathogenic variants of DNA repair genes not typically associated with colorectal cancer. Methods We recruited 88 patients with young-onset colorectal cancers seen at a general oncology center. Whole-exome sequencing was performed to identify variants in DNA repair and colorectal cancer predisposition genes. Pathogenic BRCA2 and PALB2 variants were analyzed using immunoblot and immunofluorescence on patient-derived lymphoblastoid cells. Results In general, our cohort displayed characteristic features of young-onset colorectal cancers. Most patients had left-sided tumors and were diagnosed at late stages. Four patients had familial adenomatous polyposis, as well as pathogenic APC variants. We identified 12 pathogenic variants evenly distributed between DNA repair and colorectal cancer predisposition genes. Six patients had pathogenic variants in colorectal cancer genes: APC (n = 4) and MUTYH monoallelic (n = 2). Another six had pathogenic variants in DNA repair genes: ATM (n = 1), BRCA2 (n = 1), PALB2 (n = 1), NTHL1 (n = 1), and WRN (n = 2). Pathogenic variants BRCA2 c.9154C>T and PALB2 c.1059delA showed deficient homologous recombination repair, evident from the impaired RAD51 nuclear localization and foci formation. Conclusion A substantial portion of pathogenic variants in young-onset colorectal cancer was found in DNA repair genes not previously associated with colorectal cancer. This may have implications for the management of patients. Further studies are needed to ascertain the enrichment of pathogenic DNA repair gene variants in colorectal cancers.

AimTo determine the expression pattern and prognostic value of heparan sulfate in gastric cancer.MethodThe 10E4 antiheparan sulfate monoclonal antibody was used to examine the expression pattern of heparan sulfate in tissue microarrays consisting of 162 cases of gastric carcinoma by immunohistochemistry. The immunoreactivities of both epithelial and stromal components of the specimens were examined and analysed statistically for significant associations with clinicopathological parameters, including histological grade of the tumour, extent of cancer infiltration and presence of lymph-node metastases, lymphovascular invasion, perineural invasion, perforation of gastric wall and stromal reaction. The potential use of heparan sulfate as a predictive factor for patient survival was also evaluated.ResultsReduced expression of heparan sulfate in the epithelial component was associated with higher histological grades of gastric cancer as well as the presence of more extensive tumour infiltration. Furthermore, this decrease in heparan sulfate expression was found to be predictive of reduced patient survival after tumour recurrence.ConclusionThe data suggest that heparan sulfate may play an important role in regulating the biology of gastric cancer, and that it may be a useful prognostic marker of this tumour.