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The purpose of this study was to investigate the effect of chemoresistant cancer-associated fibroblasts (R-CAFs) against cisplatin (DDP) on colorectal cancer (CRC) progression. First, clinical tissue samples of chemoresistant or chemosensitive CRC patients were collected to isolate R-CAFs or chemosensitive CAFs (S-CAFs), respectively. HT29 cells or HUVECs were co-cultured with R-CAFs by transwell device. Then the proliferation and apoptosis of HT29 cells were detected with Cell Counting Kit-8 (CCK-8) and flow cytometry. Transwell assay and tube formation assay was used to detect the migration and angiogenesis of HUVECs. In addition, a colorectal cancer transplantation model was established subcutaneously in nude mice by injecting stably transfected HT29 cells and exosomes from different CAF groups, and then the tumor volume and weight were measured and recorded. Hematoxylin and eosin staining, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) staining were performed to characterize the histopathological characteristics and apoptosis level of tumor tissues, respectively. S-CAFs and R-CAFs were isolated successfully. HT29 cell co-culture with R-CAFs significantly affected the proliferation and apoptosis of HT29 cells. Exosomes derived from R-CAFs (R-CAFs-Exo) were delivered to HT29 cells, which could induce viability, suppress apoptosis and accelerate the angiogenesis of CRC. In addition, VEGFA was highly expressed in R-CAFs-Exo, which might indicate that R-CAFs could transmit VEGFA through exosomes. Overexpressed VEGFA in R-CAFs apparently regulates the viability, apoptosis, DDP resistance, and angiogenesis of CRC. In-vivo experiments confirmed that R-CAFs-Exo promoted the progression of CRC and DDP resistance by delivering VEGFA. R-CAFs-derived exosomes promote the viability, apoptosis, DDP resistance, and angiogenesis of CRC by delivering VEGFA.

As a hot topic today, ferroptosis is closely involved in the progression and treatment of cancer. Accordingly, we built a prognostic model around ferroptosis to predict the overall survival of OSCC patients. We used up to 6 datasets from 3 different databases to ensure the credibility of the model. Then, through differentially expressed, Univariate Cox, and Lasso regression analyses, a model composed of nine prognostic-related differently expressed ferroptosis-related genes (CISD2, DDIT4, CA9, ALOX15, ATG5, BECN1, BNIP3, PRDX5 and MAP1LC3A) were constructed. Moreover, Kaplan–Meier curves, Receiver Operating Characteristic curves and principal component analysis used to verify the model's predictive ability showed the model's superiority. To deeply understand the mechanism of ferroptosis affecting the occurrence, development and prognosis of OSCC, we performed enrichment analysis in different risk groups identified by the model. The results showed that numerous TP53-related, immune-related and ferroptosis-related functions and pathways were enriched. Further immune microenvironment analysis and mutation analysis have once again revealed the correlation between risk score and immunity and TP53 mutation. Finally, the correlation between risk score and OSCC clinical treatment, as well as Nomogram show the brilliant clinical application prospects of the prognostic model.

BACKGROUND The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has displayed superior clinical effect in metastatic castration-resistant prostate cancer (mCRPC) patients with the homologous recombination repair ( HRR ) genes mutations. However, when a patient’s tumor tissue volume is insufficient for genomic profiling of HRR gene mutations, circulating tumor DNA (ctDNA) may be useful in helping to determine and monitor the efficacy of olaparib, as well as in abiraterone-combination treatment, and for understanding any resistance mechanism related to such mutations. CASE SUMMARY A 61-year-old man who was diagnosed with metastatic prostate adenocarcinoma was initially hormone sensitivity, showing high Gleason score (5 + 5 = 10) and absolute positive rate (14/14 biopsied specimens). Following failure of several standard therapies, the patient progressed to mCRPC. Surprisingly, the patient showed good response to olaparib-abiraterone-prednisone combination treatment (an androgen-deprivation therapy, provided as the ‘final choice’ in China). Serum total prostate-specific antigen (TPSA) level reduced and symptoms remitted for 4 months. However, thereafter, serum TPSA levels began slowly increasing, indicating development of olaparib resistance. Subsequent comprehensive genomic profiling of ctDNA, screening 508 cancer-related genes by next-generation sequencing, identified 10 somatic variants as well as 3 copy number alterations. Two identified reverse missense mutations in partner and localizer of BRCA2 ( PALB2 ) may have recovered the reading frame, restoring function of the primary germline PALB2 mutation and causing resistance to the PARP inhibitor olaparib. CONCLUSION Reverse mutations in PALB2 , discovered via genomic profiling of ctDNA, may represent a potential resistance mechanism against olaparib in mCRPC.

BackgroundFerroptosis, a novel form of regulating cell death, is related to various cancers. However, the role of ferroptosis-related genes (FRGs) on the occurrence and development of colon cancer (CC) needs to be further elucidated.MethodCC transcriptomic and clinical data were downloaded from TCGA and GEO databases. The FRGs were obtained from the FerrDb database. The consensus clustering was performed to identify the best clusters. Then, the entire cohort was randomly divided into the training and testing cohorts. Univariate Cox, LASSO regression and multivariate Cox analyses were used to construct a novel risk model in training cohort. The testing and the merged cohorts were performed to validate the model. Moreover, CIBERSORT algorithm analyze TIME between high- and low- risk groups. The immunotherapy effect was evaluated by analyzing the TIDE score and IPS between high- and low- risk groups. Lastly, RT-qPCR were performed to analyze the expression of the three prognostic genes, and the 2-years OS and DFS between the high- and low- risk groups of 43 clinical CC samples to further validate the value of the risk model.ResultsSLC2A3, CDKN2A, and FABP4 were identified to construct a prognostic signature. Kaplan–Meier survival curves showed that OS between the high- and low-risk groups were statistically significant (pmerged<0.001, ptraining<0.001, ptesting<0.001). TIDE score and IPS were higher in the high-risk group (pTIDE<0.005, pDysfunction<0.005, pExclusion<0.001, pmAb-CTLA-4 = 3e-08, pmAb-PD-1 = 4.1e-10). The clinical samples were divided into high- and low- risk groups according to the risk score. There was a statistical difference in DFS (p=0.0108).ConclusionThis study established a novel prognostic signature and provided more insight into the immunotherapy effect of CC.