Pancreatic ductal adenocarcinoma (PDAC) is rich in dense fibrotic stroma that are composed of extracellular matrix (ECM) proteins. A disruption of the balance between ECM synthesis and secretion and the altered expression of matrix remodeling enzymes lead to abnormal ECM dynamics in PDAC. This pathological ECM promotes cancer growth, survival, invasion, and alters the behavior of fibroblasts and immune cells leading to metastasis formation and chemotherapy resistance, which contribute to the high lethality of PDAC. Additionally, recent evidence highlights that ECM, as a major structural component of the tumor microenvironment, is a highly dynamic structure in which ECM proteins establish a physical and biochemical niche for cancer stem cells (CSCs). CSCs are characterized by self-renewal, tumor initiation, and resistance to chemotherapeutics. In this review, we will discuss the effects of the ECM on tumor biological behavior and its molecular impact on the fundamental signaling pathways in PDAC. We will also provide an overview of how the different ECM components are able to modulate CSCs properties and finally discuss the current and ongoing therapeutic strategies targeting the ECM. Given the many challenges facing current targeted therapies for PDAC, a better understanding of molecular events involving the interplay of ECM and CSC will be key in identifying more effective therapeutic strategies to eliminate CSCs and ultimately to improve survival in patients that are suffering from this deadly disease.

Background: Total mesorectal excision following neoadjuvant chemoradiotherapy (nCRT) is recommended in the latest treatment of locally advanced rectal cancer (LARC).Objective: To predict whether patients with LARC can achieve pathologic complete response (pCR), comparing MRI‐based radiomics between before and after neoadjuvant radiotherapy (nRT) was performed.Methods: One hundred and sixty‐five MRI‐based radiomics features in axial T2‐weighted images were obtained quantitatively from Imaging Biomarker Explorer Software. The specific features of conventional and developing radiomics were selected with the analysis of least absolute shrinkage and selection operator logistic regression, of which the predictive performance was analyzed with receiver operating curve and calibration curve, and applied to an independent cohort.Results: One hundred and thirty‐one target patients were enrolled in the present study. A radiomics signature founded on seven radiomics features was generated in the primary cohort. A remarkable difference about Rad‐score between pCR and non‐pCR group occurred in both of primary (P < .001) or validation cohorts (P < .001). The value of area under the curves was 0.92 (95% CI, 0.86‐0.99) and 0.87 (95% CI, 0.74‐1.00) in the primary and validation cohorts, respectively. The Rad‐score (OR = 23.581; P < .001) from multivariate logistic regression analysis was significant as an independent factor of pCR.Conclusion: Our predictive model based on radiomics features was an independent predictor for pCR in LARC and could be a candidate in clinical practice.

Objective: Pancreatic cancer is one of the most lethal human malignancies. Gemcitabine is widely used to treat pancreatic cancer, and the resistance to chemotherapy is the major difficulty in treating the disease. N⁶-methyladenosine (m⁶A) modification, which regulates RNA splicing, stability, translocation, and translation, plays critical roles in cancer physiological and pathological processes. METTL14, an m6A Lmethyltransferase, was found deregulated in multiple cancer types. However, its role in gemcitabine resistance in pancreatic cancer remains elusive.Methods: The mRNA and protein level of m⁶A modification associated genes were assessed by QRT-PCR and western blotting. Then, gemcitabine‐resistant pancreatic cancer cells were established. The growth of pancreatic cancer cells were analyzed using CCK8 assay and colony formation assay. METTL14 was depleted by using shRNA. The binding of p65 on METTL14 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Protein level of deoxycytidine kinase (DCK) and cytidine deaminase (CDA) was evaluated by western blotting. In vivo experiments were conducted to further confirm the critical role of METTL14 in gemcitabine resistance.Results: We found that gemcitabine treatment significantly increased the expression of m⁶A methyltransferase METTL14, and METTL14 was up-regulated in gemcitabine-resistance human pancreatic cancer cells. Suppression of METTL14 obviously increased the sensitivity of gemcitabine in resistant cells. Moreover, we identified that transcriptional factor p65 targeted the promoter region of METTL14 and up-regulated its expression, which then increased the expression of cytidine deaminase (CDA), an enzyme inactivates gemcitabine. Furthermore, in vivo experiment showed that depletion of METTL14 rescue the response of resistance cell to gemcitabine in a xenograft model.Conclusion: Our study suggested that METTL14 is a potential target for chemotherapy resistance in pancreatic cancer.

Background and Aims: The aim of this study was to analyse the landscape of publications on rectal cancer (RC) over the past 25 years by machine learning and semantic analysis. Methods: Publications indexed in PubMed under the Medical Subject Headings (MeSH) term ‘Rectal Neoplasms’ from 1994 to 2018 were downloaded in September 2019. R and Python were used to extract publication date, MeSH terms and abstract from the metadata of each publication for bibliometric assessment. Latent Dirichlet allocation was applied to analyse the text from the articles’ abstracts to identify more specific research topics. Louvain algorithm was used to establish a topic network resulting in identifying the relationship between the topics. Results: A total of 23,492 papers published were identified and analysed in this study. The changes of research focus were analysed by the changing of MeSH terms. Studied contents extracted from the publications were divided into five areas, including surgical intervention, radiotherapy and chemotherapy intervention, clinical case management, epidemiology and cancer risk as well as prognosis studies. Conclusions: The number of publications indexed on RC has expanded rapidly over the past 25 years. Studies on RC have mainly focused on five areas. However, studies on basic research, postoperative quality of life and cost-effective research were relatively lacking. It is predicted that basic research, inflammation and some other research fields might become the potential hotspots in the future.

Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (m⁶A), is involved in the tumorigenesis of many types of cancer. As one of the largest m⁶A methyltransferase complex components, KIAA1429 bridges the catalytic m⁶A methyltransferase components, such as METTL3. In gastric cancer, KIAA1429 was reported to promote cell proliferation. However, whether KIAA1429 is involved in the resistance of gastric cancer to cisplatin remains unclear. Here, we generated cisplatin resistant gastric cancer cell lines, and compared the m⁶A content between resistant cells and wild type cells. The m⁶A content as well as KIAA1429 expression are higher in resistant cells. Interestingly, the expression of KIAA1429 was significantly increased after cisplatin treatment. We then used shRNA to knockdown KIAA1429 and found that resistant cells responded more to cisplatin treatment after KIAA1429 depletion, while overexpression of KIAA1429 decreased the sensitivity. Moreover, we identified a putative p65 binding site on the promoter area of KIAA1429 and ChIP assay confirmed the binding. p65 depletion decreased the expression of KIAA1429. YTHDF1 is the most abundant m⁶A “reader” that interacts with m⁶A modified mRNA. Mechanistically, YTHDF1 was recruited to the 3′-untranslated Region (3′-UTR) of transcriptional factor, FOXM1 by KIAA1429 and stabilized FOXM1 mRNA. More importantly, KIAA1429 knockdown increased the sensitivity of resistant cells to cisplatin in vivo. In conclusion, our results demonstrated that KIAA1429 facilitated cisplatin resistance by stabilizing FOXM1 mRNA in gastric cancer cells.

N6-methyladenosine (m6A) modifications of RNAs are involved in various aspects of colorectal carcinogenesis via regulation of mRNA stability, splicing, and translation. KIAA1429, an m6A methyltransferase, was found deregulated in multiple cancer types. However, its role in colorectal cancer remains elusive. By analyzing TCGA and GEPIA database, we found that KIAA1429 in colorectal cancer was highly expressed. In addition, we used immunohistochemistry, western blotting, and QRT-PCR to detect the expression of KIAA1429 in colorectal cancer samples and cell lines, and we found that KIAA1429 was overexpressed in colorectal cancer sample and cell line. Functionally, silencing of KIAA1429 by shRNA in colorectal cancer cell lines resulted in decreased cell proliferation, colony formation, and migration. On the contrary, overexpression of KIAA1429 increased cell proliferation, colony formation, and migration. Further mechanism analysis demonstrated that KIAA1429 increased the expression of SIRT1 via regulating its mRNA stability in an m6A-dependent manner. More importantly, in vivo experiment showed that depletion of KIAA1429 significantly inhibited colorectal tumor growth. In conclusion, our results suggested that the m6A methyltransferase KIAA1429 promotes the growth and motility of colorectal cancer and could be a potent therapeutic target.