Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with high morbidity and mortality worldwide. To date, limited therapeutic achievements targeting cell proliferation and related mechanisms has led researchers to focus on the microenvironment where pancreatic cancers develop. The anomalous proliferation of stromal cells, such as pancreatic stellate cells, and an increased deposition of altered matrix proteins create an environment that facilitates tumor growth, metastasis and drug resistance. Here, we summarize our understanding of recent advances in research about the role of fibrosis in pancreatic cancer progression, with particular emphasize on the involvement of fibrotic machineries such as wound healing, extra cellular matrix degradation, and epithelial-to-mesenchymal transition. The precise influence of these mechanisms on the biological behaviors and growth of cancer cells has great impact on clinical therapy and therefore deserves more attention. We also discuss the role of various stromal components in conferring drug resistance to PDAC which further worsening the pessimistic disease prognosis. A more in depth understanding of cancer-stroma crosstalk within the tumor microenvironment and stroma based clinical and translational therapies may provide new therapeutic strategies for the prevention of pancreatic cancer progression.

Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in view the significant role of metabolic alterations in cancer, we hypothesized that a ketogenic diet may diminish glycolytic flux in tumor cells to alleviate cachexia syndrome and, hence, may provide an efficient therapeutic strategy. We observed reduced glycolytic flux in tumor cells upon treatment with ketone bodies. Ketone bodies also diminished glutamine uptake, overall ATP content, and survival in multiple pancreatic cancer cell lines, while inducing apoptosis. A decrease in levels of c-Myc, a metabolic master regulator, and its recruitment on glycolytic gene promoters, was in part responsible for the metabolic phenotype in tumor cells. Ketone body-induced intracellular metabolomic reprogramming in pancreatic cancer cells also leads to a significantly diminished cachexia in cell line models. Our mouse orthotopic xenograft models further confirmed the effect of a ketogenic diet in diminishing tumor growth and cachexia. Thus, our studies demonstrate that the cachectic phenotype is in part due to metabolic alterations in tumor cells, which can be reverted by a ketogenic diet, causing reduced tumor growth and inhibition of muscle and body weight loss.

Aberrant expression of CA125/MUC16 is associated with pancreatic ductal adenocarcinoma (PDAC) progression and metastasis. However, knowledge of the contribution of MUC16 to pancreatic tumorigenesis is limited. Here, we show that MUC16 expression is associated with disease progression, basal-like and squamous tumor subtypes, increased tumor metastasis, and short-term survival of PDAC patients. MUC16 enhanced tumor malignancy through the activation of AKT and GSK3β oncogenic signaling pathways. Activation of these oncogenic signaling pathways resulted in part from increased interactions between MUC16 and EGF-type receptors, which were enhanced for aberrant glycoforms of MUC16. Treatment of PDAC cells with mAb AR9.6 significantly reduced MUC16 induced oncogenic signaling. mAb AR9.6 binds to a unique conformational epitope on MUC16, which is influenced by O-glycosylation. Additionally, treatment of PDAC tumor-bearing mice with either mAb AR9.6 alone or in combination with gemcitabine significantly reduced tumor growth and metastasis. We conclude that the aberrant expression of MUC16 enhances PDAC progression to an aggressive phenotype by modulating oncogenic signaling through ErbB receptors. Anti-MUC16 mAb AR9.6 blocks oncogenic activities and tumor growth and could be a novel immunotherapeutic agent against MUC16 mediated PDAC tumor malignancy.

Aberrant expression of Sialyl‐Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Co re 1 s ynthase specific m olecular c haperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O‐glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial‐to‐mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re‐expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O‐glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties.

Cellular signaling pathways are intricately regulated to maintain homeostasis. During cancer progression, these mechanisms are manipulated to become harmful. O-glycosylation, a crucial post-translational modification, is one such pathway that can lead to multiple isoforms of glycoproteins. The Tn (GalNAc-O-Ser/Thr) and Sialyl Tn (STn; Neu5Ac-GalNAc-O-Ser/Thr) antigens resulting from the incomplete synthesis of fully branched O-glycan chains on proteins contribute to disease progression in the pancreas and other gastrointestinal cancers. The tumor microenvironment (TME) is a major constituent of tumors and a key modulator of their behavior. Multiple cellular and secretory components of the TME dictate the development and metastasis of tumors. Immune cells like macrophages, natural killer (NK) cells, dendritic cells, B and T lymphocytes are a part of the tumor “immune” microenvironment (TIME). The expression of the Tn and STn antigens on tumors has been found to regulate the function of these immune cells and alter their normal antitumor cytotoxic role. This is possible through multiple cell intrinsic and extrinsic signaling pathways, elaborated in this review. Studying the interaction between Tn/STn antigens and the TIME of gastrointestinal cancers can help develop better and more robust therapies that can counteract immunosuppressive mechanisms to sensitize these tumors to anticancer therapies.