Secretory Trefoil Factor 1 (TFF1) promotes gemcitabine resistance through chemokine receptor CXCR4 in Pancreatic Ductal Adenocarcinoma.

Gemcitabine is the first-line treatment option for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, the frequent adoption of resistance to gemcitabine by cancer cells poses a significant challenge in treating this aggressive disease. In this study, we focused on analyzing the role of trefoil factor 1 (TFF1) in gemcitabine resistance in PDAC. Analysis of PDAC TCGA and cell line datasets indicated an enrichment of TFF1 in the gemcitabine-resistant classical subtype and suggested an inverse correlation between TFF1 expression and sensitivity to gemcitabine treatment. The genetic ablation of TFF1 in PDAC cells enhanced their sensitivity to gemcitabine treatment in both in vitro and in vivo tumor xenografts. The biochemical studies revealed that TFF1 contributes to gemcitabine resistance through enhanced stemness, increasing migration ability of cancer cells, and induction of anti-apoptotic genes. We further pursued studies to predict possible receptors exerting TFF1-mediated gemcitabine resistance. Protein-protein docking investigations with BioLuminate software revealed that TFF1 binds to the chemokine receptor CXCR4, which was supported by real-time binding analysis of TFF1 and CXCR4 using SPR studies. The exogenous addition of TFF1 increased the proliferation and migration of PDAC cells through the pAkt/pERK axis, which was abrogated by treatment with a CXCR4-specific antagonist AMD3100. Overall, the present study demonstrates the contribution of the TFF1-CXCR4 axis in imparting gemcitabine resistance properties to PDAC cells.

Chimeric antibody targeting unique epitope on onco-mucin16 reduces tumor burden in pancreatic and lung malignancies.

Aberrantly expressed onco-mucin 16 (MUC16) and its post-cleavage generated surface tethered carboxy-terminal (MUC16-Cter) domain are strongly associated with poor prognosis and lethality of pancreatic (PC) and non-small cell lung cancer (NSCLC). To date, most anti-MUC16 antibodies are directed towards the extracellular domain of MUC16 (CA125), which is usually cleaved and shed in the circulation hence obscuring antibody accessibility to the cancer cells. Herein, we establish the utility of targeting a post-cleavage generated, surface-tethered oncogenic MUC16 carboxy-terminal (MUC16-Cter) domain by using a novel chimeric antibody in human IgG1 format, ch5E6, whose epitope expression directly correlates with disease severity in both cancers. ch5E6 binds and interferes with MUC16-associated oncogenesis, suppresses the downstream signaling pFAK(Y397)/p-p70S6K(T389)/N-cadherin axis and exert antiproliferative effects in cancer cells, 3D organoids, and tumor xenografts of both PC and NSCLC. The robust clinical correlations observed between MUC16 and N-cadherin in patient tumors and metastatic samples imply ch5E6 potential in targeting a complex and significantly occurring phenomenon of epithelial to mesenchymal transition (EMT) associated with disease aggressiveness. Our study supports evaluating ch5E6 with standard-of-care drugs, to potentially augment treatment outcomes in malignancies inflicted with MUC16-associated poor prognosis.

A Novel HOXA10-Associated 5-Gene-Based Prognostic Signature for Stratification of Short-term Survivors of Pancreatic Ductal Adenocarcinoma.

PURPOSE: Despite the significant association of molecular subtypes with poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC), few efforts have been made to identify the underlying pathway(s) responsible for this prognosis. Identifying a clinically relevant prognosis-based gene signature may be the key to improving patient outcomes. EXPERIMENTAL DESIGN: We analyzed the transcriptomic profiles of treatment-naïve surgically resected short-term survivor (STS) and long-term survivor (LTS) tumors (GSE62452) for expression and survival, followed by validation in several datasets. These results were corroborated by IHC analysis of PDAC-resected STS and LTS tumors. The mechanism of this differential survival was investigated using CIBERSORT and pathway analyses. RESULTS: We identified a short-surviving prognostic subtype of PDAC with a high degree of significance (P = 0.018). One hundred thirty genes in this novel subtype were found to be regulated by a master regulator, homeobox gene HOXA10, and a 5-gene signature derived from these genes, including BANF1, EIF4G1, MRPS10, PDIA4, and TYMS, exhibited differential expression in STSs and a strong association with poor survival. This signature was further associated with the proportion of T cells and macrophages found in STSs and LTSs, demonstrating a potential role in PDAC immunosuppression. Pathway analyses corroborated these findings, revealing that this HOXA10-driven prognostic signature is associated with immune suppression and enhanced tumorigenesis. CONCLUSIONS: Overall, these findings reveal the presence of a HOXA10-associated prognostic subtype that can be used to differentiate between STS and LTS patients of PDAC and inform on the molecular interactions that play a role in this poor prognosis.

Implications of prognosis-associated genes in pancreatic tumor metastasis: lessons from global studies in bioinformatics.

Pancreatic cancer (PC) is a highly lethal malignancy with a 5-year survival rate of 10%. The occurrence of metastasis, among other hallmarks, is the main contributor to its poor prognosis. Consequently, the elucidation of metastatic genes involved in the aggressive nature of the disease and its poor prognosis will result in the development of new treatment modalities for improved management of PC. There is a deep interest in understanding underlying disease pathology, identifying key prognostic genes, and genes associated with metastasis. Computational approaches, which have become increasingly relevant over the last decade, are commonly used to explore such interests. This review aims to address global studies that have employed global approaches to identify prognostic and metastatic genes, while highlighting their methods and limitations. A panel of 48 prognostic genes were identified across these studies, but only five, including ANLN, ARNTL2, PLAU, TOP2A, and VCAN, were validated in multiple studies and associated with metastasis. Their association with metastasis has been further explored here, and the implications of these genes in the metastatic cascade have been interpreted.

Odyssey of trefoil factors in cancer: Diagnostic and therapeutic implications.

Trefoil factors 1, 2, and 3 (TFFs) are a family of small secretory molecules involved in the protection and repair of the gastrointestinal tract (GI). TFFs maintain and restore epithelial structural integrity via transducing key signaling pathways for epithelial cell migration, proliferation, and invasion. In recent years, TFFs have emerged as key players in the pathogenesis of multiple diseases, especially cancer. Initially recognized as tumor suppressors, emerging evidence demonstrates their key role in tumor progression and metastasis, extending their actions beyond protection. However, to date, a comprehensive understanding of TFFs' mechanism of action in tumor initiation, progression and metastasis remains obscure. The present review discusses the structural, functional and mechanistic implications of all three TFF family members in tumor progression and metastasis. Also, we have garnered information from studies on their structure and expression status in different organs, along with lessons from their specific knockout in mouse models. In addition, we highlight the emerging potential of using TFFs as a biomarker to stratify tumors for better therapeutic intervention.