Search

Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence has demonstrated that the tumor cell functions are modulated by its microenvironment, compromising fibroblasts, extracellular matrices, microbiome, immune cells, and the enteric nervous system. Along with the tumor microenvironment components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell–intrinsic and –extrinsic factors during tumor progression is critical for developing new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Despite the ongoing advances in interventional strategies (surgery, chemotherapy, radiotherapy, and immunotherapy) for managing pancreatic ductal adenocarcinoma (PDAC), the development of therapy refractory phenotypes remains a significant challenge. Resistance to various therapeutic modalities in PDAC emanates from a combination of inherent and acquired factors and is attributable to cancer cell-intrinsic and -extrinsic mechanisms. The critical determinants of therapy resistance include oncogenic signaling and epigenetic modifications that drive cancer cell stemness and metabolic adaptations, CAF-mediated stromagenesis that results in ECM deposition altered mechanotransduction, and secretome and immune evasion. We reviewed the current understanding of these multifaceted mechanisms operating in the PDAC microenvironment, influencing the response to chemotherapy, radiotherapy, and immunotherapy regimens. We then describe how the lessons learned from these studies can guide us to discover novel therapeutic regimens to prevent, delay, or revert resistance and achieve durable clinical responses. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely cancer-associated fibroblasts (CAFs), play a major role in PDAC progression. We analyzed whether CAFs influence acinar cells and impact PDAC initiation, that is, acinar-to-ductal metaplasia (ADM). ADM connection with PDAC pathophysiology is indicated, but not yet established. We hypothesized that CAF secretome might play a significant role in ADM in PDAC initiation. Mouse and human acinar cell organoids, acinar cells cocultured with CAFs and exposed to CAF-conditioned media, acinar cell explants, and CAF cocultures were examined by means of quantitative reverse transcription polymerase chain reaction, RNA sequencing, immunoblotting, and confocal microscopy. Data from liquid chromatography with tandem mass spectrometry analysis of CAF–conditioned medium and RNA sequencing data of acinar cells post–conditioned medium exposure were integrated using bioinformatics tools to identify the molecular mechanism for CAF-induced ADM. Using confocal microscopy, immunoblotting, and quantitative reverse transcription polymerase chain reaction analysis, we validated the depletion of a key signaling axis in the cell line, acinar explant coculture, and mouse cancer-associated fibroblasts (mCAFs). A close association of acino–ductal markers (Ulex europaeus agglutinin 1, amylase, cytokeratin-19) and mCAFs (α-smooth muscle actin) in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1Cre (KPC) and LSL-KrasG12D/+; Pdx1Cre (KC) autochthonous progression tumor tissue was observed. Caerulein treatment–induced mCAFs increased cytokeratin-19 and decreased amylase in wild-type and KC pancreas. Likewise, acinar-mCAF cocultures revealed the induction of ductal transdifferentiation in cell line, acinar-organoid, and explant coculture formats in WT and KC mice pancreas. Proteomic and transcriptomic data integration revealed a novel laminin α5/integrinα4/stat3 axis responsible for CAF-mediated acinar-to-ductal cell transdifferentiation. Results collectively suggest the first evidence for CAF-influenced acino–ductal phenotypic switchover, thus highlighting the tumor microenvironment role in pancreatic carcinogenesis inception. [Display omitted] Pancreatic cancer inception and early detection remain elusive. Complex cellular crosstalk transforming normal cells toward tumor development by means of novel cell signaling mechanism has been identified as the potential culprit. [ABSTRACT FROM AUTHOR]

Abstract Pancreatic cancer is a highly lethal malignancy. Lack of early diagnostic markers makes timely detection of pancreatic cancer a highly challenging endeavor. Exosomes have emerged as information-rich cancer specific biomarkers. However, characterization of tumor-specific exosomes has been challenging. This study investigated the proof of principle that exosomes could be used for the detection of pancreatic cancer. Label-free analysis of exosomes purified from normal and pancreatic cancer cell lines was performed using surface enhanced Raman Spectroscopy (SERS) and principal component differential function analysis (PC-DFA), to identify tumor-specific spectral signatures. This method differentiated exosomes originating from pancreatic cancer or normal pancreatic epithelial cell lines with 90% accuracy. The cell line trained PC-DFA algorithm was next applied to SERS spectra of serum-purified exosomes. This method exhibited up to 87% and 90% predictive accuracy for HC and EPC individual samples, respectively. Overall, our study identified utility of SERS spectral signature for deciphering exosomal surface signature. Graphical Abstract The present study utilizes exosomes purified from pancreatic cancer and pancreatic epithelial cell lines and surface enhanced Raman spectroscopy (SERS) spectra to train an algorithm by Principle Component-Differential Functional Analysis (PC-DFA). This trained PC-DFA algorithm was subsequently applied to SERS spectra to characterize exosomes as originating from pancreatic patient or healthy patient serum with up to 90% accuracy. Unlabelled Image [ABSTRACT FROM AUTHOR]

Background & Aims Pancreatic ductal adenocarcinomas (PDACs) produce higher levels of truncated O-glycan structures (such as Tn and sTn) than normal pancreata. Dysregulated activity of core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1 (C1GALT1) leads to increased expression of these truncated O-glycans. We investigated whether and how truncated O-glycans contributes to the development and progression of PDAC using mice with disruption of C1galt1. Methods We crossed C1galt1 floxed mice (C1galt1 loxP/loxP ) with Kras G12D/+ ; Trp53 R172H/+ ; Pdx1-Cre (KPC) mice to create KPCC mice. Growth and progression of pancreatic tumors were compared between KPC and KPCC mice; pancreatic tissues were collected and analyzed by immunohistochemistry; immunofluorescence; and Sirius red, alcian blue, and lectin staining. We used the CRISPR/Cas9 system to disrupt C1GALT1 in human PDAC cells (T3M4 and CD18/HPAF) and levels of O-glycans were analyzed by lectin blotting, mass spectrometry, and lectin pulldown assay. Orthotopic studies and RNA sequencing analyses were performed with control and C1GALT1 knockout PDAC cells. C1GALT1 expression was analyzed in well-differentiated (n = 36) and poorly differentiated (n = 23) PDAC samples by immunohistochemistry. Results KPCC mice had significantly shorter survival times (median 102 days) than KPC mice (median 200 days) and developed early pancreatic intraepithelial neoplasias at 3 weeks, PDAC at 5 weeks, and metastasis at 10 weeks compared with KPC mice. Pancreatic tumors that developed in KPCC mice were more aggressive (more invasive and metastases) than those in KPC mice, had a decreased amount of stroma, and had increased production of Tn. Poorly differentiated PDAC specimens had significantly lower levels of C1GALT1 than well-differentiated PDACs. Human PDAC cells with knockout of C1GALT1 had aberrant glycosylation of MUC16 compared with control cells and increased expression of genes that regulate tumorigenesis and metastasis. Conclusions In studies of KPC mice with disruption of C1galt1 , we found that loss of C1galt1 promotes development of aggressive PDACs and increased metastasis. Knockout of C1galt1 leads to increased tumorigenicity and truncation of O-glycosylation on MUC16, which could contribute to increased aggressiveness. Graphical abstract [ABSTRACT FROM AUTHOR]