Targeted inhibition of CHKα and mTOR in models of pancreatic ductal adenocarcinoma: A novel regimen for metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy for which there are currently no effective anti-metastatic therapies. Herein, we employed single-cell RNA sequencing and metabolomics analysis to demonstrate that metastatic cells highly express focal adhesion kinase (FAK), which promotes metastasis by remodeling choline kinase α (CHKα)-dependent choline metabolism. We designed a novel CHKα inhibitor, CHKI-03, and verified its efficacy in inhibiting metastasis in multiple preclinical models. Classical and newly synthesized small-molecule inhibitors have previously been used to assess the therapeutic potential of targeting mTOR and CHKα in various animal models. Mechanistically, FAK activated mTOR and its downstream HIF-1α, thereby elevating CHKα expression and promoting the proliferation, migration, and invasion of PDAC cells, as well as tumor growth and metastasis. Consistently, high expression levels of both FAK and CHKα are correlated with poor prognosis in patients with PDAC. Notably, CHK1-03 inhibited CHKα expression and also suppressed mTORC1 phosphorylation, disrupting the mTORC1-CHKα positive feedback loop. In addition, the combination of CHKI-03 and the mTORC1 inhibitor rapamycin synergistically inhibited tumor growth and metastasis in PDX models. The combination of CHKI-03 and rapamycin demonstrates considerable therapeutic efficacy in PDO models resistant to gemcitabine. Our findings reveal a pivotal mechanism underlying PDAC metastasis regulated by mTORC1-CHKα loop-dependent choline metabolism reprogramming, highlighting the therapeutic potential of this novel regimen for treating PDAC metastasis.

FGFR3 Nuclear Translocation Contributes to Proliferative Potential and Poor Prognosis in Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Fibroblast growth factor receptor 3 (FGFR3) was revealed to have divergent, even opposite roles in different neoplasms. In pancreatic ductal adenocarcinoma (PDAC), its impact on biological behavior and prognosis was not well elucidated. METHODS: Fibroblast growth factor receptor 3 was downregulated by RNA interference to explore its impact on cell proliferative proclivity in PDAC cells. Furthermore, tissue microarray-based immunohistochemistry for FGFR3 was performed in 326 patients with PDAC who underwent radical resection, and its clinicopathologic and prognostic implications were then evaluated. RESULTS: First, successful FGFR3 knockdown remarkably decreased its expression, cell proliferation, and S-phase ratio in the cell cycle in 2 PDAC cell lines, BxPC-3 and AsPC-1. Meanwhile, alterations in p-Akt, cyclin D1, cyclin B1, and p21 were also observed. Subsequently, high nuclear FGFR3 expression, but not cytoplasmic, was significantly common in tumor tissues and positively associated with N stage and dismal overall survival in the entire cohort. In addition, nuclear FGFR3 expression was also prognostic in 10 of 14 subsets. Univariate and multivariate Cox regression analyses identified nuclear expression of FGFR3 as an independent prognosticator in the entire cohort. CONCLUSIONS: Our data showed that FGFR3 nuclear translocation contributes to cell proliferative potential and predicts poor long-term prognosis in PDAC after surgical resection.

Expression and Prognostic Value of Small Mothers Against Decapentaplegic 7, Matrix Metalloproteinase 2, and Matrix Metalloproteinase 9 in Resectable Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: Thus far, expression, clinicopathologic, and prognostic implication of small mothers against decapentaplegic 7 (Smad7), matrix metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9) in pancreatic ductal adenocarcinoma (PDAC) were rarely investigated or controversial. METHODS: Expression of Smad7, MMP2, and MMP9 was detected using immunohistochemistry in tissue microarrays based on 322 patients with curatively resected PDAC. Their expression pattern, clinicopathologic, and prognostic relevance were further evaluated. RESULTS: Smad7 expression was found to be lower in tumor than in adjacent nontumor tissues, whereas tumoral MMP2 and MMP9 staining scores were much higher than in adjacent nontumor ones. Furthermore, Smad7 was negatively associated with serum carbohydrate antigen 19-9 level. Univariate survival analyses showed that patients with high Smad7 tumors had significantly better disease-specific survival (P = 0.0007), whereas MMP2 and MMP9 predicted poor disease-specific survival (P = 0.0211 and 0.0404). In multivariate Cox regression test, Smad7 was an independent prognostic indicator (P = 0.021). In addition, these 3 proteins were also prognostic in many subgroups. CONCLUSIONS: Smad7 and MMP2/9 significantly predict good or poor prognosis in resectable PDAC, respectively. Therefore, the genes might serve as a tool or targets for molecular therapy in PDAC.

Clinicopathological and prognostic significance of ubiquitin-specific peptidase 15 and its relationship with transforming growth factor-ß receptors in patients with pancreatic ductal adenocarcinoma.

BACKGROUND AND AIM: Ubiquitin-specific peptidase 15 (USP15) has been correlated to aggressive oncogenic behavior in several types of carcinomas, but its function in pancreatic ductal adenocarcinoma (PDAC) has not been clarified. This study aimed to evaluate the clinicopathological and prognostic value of USP15 and its relationship with transforming growth factor-ß (TGF-ß) receptors (TßRs) in PDAC. METHODS: By immunohistochemical staining of tissue microarrays, the expression patterns of USP15 and TßRs were retrospectively analyzed in 287 PDAC patients who underwent radical surgical resection without neoadjuvant therapy. Cancer-specific survival was compared based on USP15 expression, and the correlations between USP15 and TßRs were analyzed. RESULTS: Ubiquitin-specific peptidase 15 expression in tumor tissues was significantly higher than that in para-tumor tissues (P < 0.0001), and high USP15 expression was associated with the pathological N (pN) stage (P = 0.033). In addition, high USP15 expression was significantly associated with shorter cancer-specific survival (P = 0.019). Univariate analyses showed that high USP15 expression (P = 0.024), a poor histopathological grade (P = 0.003), and the pN1 stage (P = 0.009) were significantly correlated with shorter survival. Although the independent prognostic value of USP15 alone was not established, the combination of USP15 and the histological grade was identified as an independent prognostic factor in multivariate analyses (P = 0.015). USP15 expression was correlated with TßR-I, TßR-II, or TßR-III expression in PDAC. CONCLUSIONS: High USP15 expression is a potential prognostic indicator in patients with PDAC, and it might affect the TGF-ß signaling pathway in PDAC.

Elevated TIAM2 expression promotes tumor progression and is associated with unfavorable prognosis in pancreatic cancer.

BACKGROUND AND AIM: As a Rac1 guanine nucleotide exchange factor, T-cell lymphoma invasion and metastasis 2 (TIAM2) has been reported to be correlated with malignant phenotypes in several cancers, but its prognostic significance and function in pancreatic ductal adenocarcinoma (PDAC) was not investigated. METHODS: The expression patterns of TIAM2 and patient survival were analyzed in a large cohort of 303 patients with radical surgical resection of PDAC, using immunohistochemical staining in tissue microarrays. Data mining was applied to evaluate TIAM2 expression and patient survival at the mRNA level. The function of TIAM2 in proliferation, motility and invasion of pancreactic cancer (PC) cells was also investigated. RESULTS: TIAM2 expression was significantly increased in PDAC compared with para-tumor tissues (p < .0001). The expression of TIAM2 was associated with histopathological grade (p = .008), tumor location (p = .013), and pathological T stage (p = .029). For survival, patients with high TIAM2 expression had significantly poor prognosis in some subgroups. In addition, multivariate analyses showed that the combination of TIAM2 and the pathological N stage largely enhanced the prognostic efficiency, and was found to be as an independent prognostic indicator in patients with PDAC. Data mining elucidated that TIAM2 mRNA expression level was increased in tumor tissues and correlated with patient survival. Furthermore, high TIAM2 expression was common in PC cells. Downregulation of TIAM2 suppressed cell proliferation, migration and invasion in PC. CONCLUSIONS: High expression of TIAM2 might be a meaningful prognostic factor for PDAC patients, and TIAM2 participates in tumor progression in PDAC.

Stroma-Targeting Therapy in Pancreatic Cancer: One Coin With Two Sides?

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with one of the worst prognoses worldwide and has an overall 5-year survival rate of only 9%. Although chemotherapy is the recommended treatment for patients with advanced PDAC, its efficacy is not satisfactory. The dense dysplastic stroma of PDAC is a major obstacle to the delivery of chemotherapy drugs and plays an important role in the progression of PDAC. Therefore, stroma-targeting therapy is considered a potential treatment strategy to improve the efficacy of chemotherapy and patient survival. While several preclinical studies have shown encouraging results, the anti-tumor potential of the PDAC stroma has also been revealed, and the extreme depletion might promote tumor progression and undermine patient survival. Therefore, achieving a balance between stromal abundance and depletion might be the further of stroma-targeting therapy. This review summarized the current progress of stroma-targeting therapy in PDAC and discussed the double-edged sword of its therapeutic effects.

Prognostic Biomarkers for Pancreatic Ductal Adenocarcinoma: An Umbrella Review.

Background: Pancreatic ductal adenocarcinoma (PDAC) leads to the majority of cancer-related deaths due to its morbidity with similar mortality. Lack of effective prognostic biomarkers are the main reason for belated post-operative intervention of recurrence which causes high mortality. Numerous systematic reviews and meta-analyses have explored the prognostic value of biomarkers in PDAC so far. In this article, we performed an umbrella review analyzing these studies to provide an overview of associations between prognostic biomarkers and PDAC survival outcome and synthesized these results to guide better clinical practice. Methods: Systematic reviews and meta-analyses investigating the associations between PDAC survival outcomes and prognostic biomarkers were acquired via the PubMed and Embase databases from inception till February 1, 2020. Associations supported by nominally statistically significant results were classified into strong, highly suggestive, suggestive, and weak based on several critical factors such as the statistical significance of summary estimates, the number of events, the estimate of the largest study included, interstudy heterogeneity, small-study effects, 95% predictive interval (PI), excess significance bias, and the results of credibility ceiling sensitivity analyses. Results: We included 41 meta-analyses containing 63 associations between PDAC survival outcomes and prognostic biomarkers. Although, none was supported by strong evidence among these associations, an association between C-reactive protein to albumin ratio (CAR) and PDAC overall survival (OS) and an association between neutrophil-lymphocyte ratio (NLR) and PDAC OS were supported by highly suggestive evidence. Otherwise, the association between lactate dehydrogenase (LDH) and PDAC OS was supported by suggestive evidence. The remaining 60 associations were supported by weak or not suggestive evidence. Conclusion: Associations between CAR or NLR and PDAC OS were supported by highly suggestive evidence. And the association between LDH and PDAC OS was supported by suggestive evidence. Although the methodological quality of the included systematic reviews and meta-analyses which were evaluated by AMSTAR2.0 is generally poor, the identification of the relatively robust prognostic biomarkers of PDAC may guide better post-operative intervention and follow-up to prolong patients' survival.

Ubiquitin-specific protease 4 predicts an unfavorable prognosis and promotes malignant behaviors in vitro in pancreatic cancer.

Ubiquitin-specific protease 4 (USP4), has been reported to participate in the progression of various cancers due to its role in post-translational modulation. However, the prognostic significance and mechanism of USP4 in pancreatic cancer (PC) have not been well elucidated before. In the present study, we found that USP4 expression was higher in PC tissues than that in adjacent normal tissues and PC patients with high level of USP4 expression have a poor prognosis via immunohistochemistry and bioinformatics analyses. In vitro study showed that knockdown of USP4 inhibited PC cells proliferation, migration and invasion. Mechanistically, USP4 can activate nuclear factor kappa-B signaling pathway via stabilizing TNF receptor associated factor 6 at its protein level to promote the ability of proliferation, migration and invasion of PC cells. The results of this study revealed that USP4 plays a tumor-promoting role in PC and can be used as a prognostic indicator and therapeutic target for patients with resected PC.

Research progress on long non-coding RNAs and their roles as potential biomarkers for diagnosis and prognosis in pancreatic cancer.

Pancreatic cancer is one of the main causes of tumor-related deaths worldwide because of its low morbidity but extremely high mortality, and is therefore colloquially known as the "king of cancer." Sudden onset and lack of early diagnostic biomarkers directly contribute to the extremely high mortality rate of pancreatic cancer patients, and also make it indistinguishable from benign pancreatic diseases and precancerous pancreatic lesions. Additionally, the lack of effective prognostic biomarkers makes it difficult for clinicians to formulate precise follow-up strategies based on the postoperative characteristics of the patients, which results in missed early diagnosis of recurrent pancreatic cancer. Long non-coding RNAs (lncRNAs) can influence cell proliferation, invasion/migration, apoptosis, and even chemoresistance via regulation of various signaling pathways, leading to pro- or anti-cancer outcomes. Given the versatile effects of lncRNAs on tumor progression, using a single lncRNA or combination of several lncRNAs may be an effective method for tumor diagnosis and prognostic predictions. This review will give a comprehensive overview of the most recent research related to lncRNAs in pancreatic cancer progression, as targeted therapies, and as biomarkers for the diagnosis and prognosis of pancreatic cancer.

Predictors of lymph node metastasis and residual tumor in early gastric cancer patients after noncurative endoscopic resection: a systematic review and meta-analysis.

BACKGROUND: It is challenging to identify the prevalence of lymph node metastasis (LNM) and residual tumor in patients with early gastric cancer (EGC) who underwent noncurative endoscopic resection (ER). This present meta-analysis was aimed to establish imperative potential predictive factors in order to select the optimal treatment method. METHODS: A systematic literature search of PubMed, Embase, and Cochrane Library databases was performed through 1 February 2019 to identify relevant studies, which investigated risk factors for LNM and residual tumor in patients with EGC who underwent noncurative ER. Eligible data were systematically reviewed through a meta-analysis. RESULTS: Overall, 12 studies investigating the risk factor of LNM were included, totaling 3015 patients, 7 of which also involved cancer residues. After the present meta-analysis, six predictors, including tumor size >30 mm, tumor invasion depth (⩾500 µm from the muscularis mucosae), macroscopic appearance, undifferentiated histopathological type, positive vertical margin, and presence of lymphovascular invasion (including lymphatic invasion and vascular invasion) were significantly associated with LNM, whereas tumor size >30 mm, positive horizontal margin, and positive vertical margin were identified as significant predictors for the risk of residual tumor. No evidence of publication bias was observed. CONCLUSIONS: Six and three variables were established as significant risk factors for LNM and residual tumor in patients with EGC who underwent noncurative ER, respectively. Patients with EGC who present these risk factors after noncurative ER are strongly suggested to receive additional surgery, while others might be suitable for strict follow-up. This might shed some new light on the selection of follow-up treatment for noncurative ER.