Pancreatic ductal adenocarcinoma is among the deadliest cancers, and its own incidence increasing. the Smo antagonist IPI926 in tumor-bearing KPC mice extended survival when coupled with gemcita-bine.79 However, IPI926 failed within a clinical trial, with worsened individual outcomes CCT129202 in comparison to chemotherapy alone, and a different Smo inhibitor, GDC 0449 (Genentech, South San Francisco, CA), provided no benefit.80 Following the disappointing clinical results, a new study in an experimental model showed that KPC mice lacking Shh expression in the epithelium progress to cancer CCT129202 faster than KPC mice expressing Shh.81 IPI926 treatment in KPC mice, this time in the absence of concurrent chemotherapy, shortened survival similarly.81 A possible clue to these contradictory results comes from a study indicating that HH signaling dosage might drive different cellular responses.74 In particular, lowering HH signaling without ablating its activity CCT129202 altogether induces expression of pro-angiogenic factors, such as VEGF and Agptl,81 known Gli targets. Further, ablation of Smo in pancreatic fibroblasts paradoxically results in a compensatory overexpression of Gli2, the main Gli activator.82 Many open questions remain regarding the role of HH signaling in pancreatic cancer. Going forward, it will be of paramount importance to identify the target genes of HH signaling, and gather an understanding of the heterogeneity of fibroblast populations in pancreatic cancer, in fact, while ablation of most fibroblasts in pancreatic cancer resulted in the development of an aggressive, sarcomatoid tumor type, this tumor was, however, sensitive to immune checkpoint inhibition, thus potentially indicating that a targeted combination approach should be developed.83 More recently, the concept of normalizing pancreatic fibroblasts has gained traction, with a study showing that high doses of vitamin D might reverse fibroblast activation status.84 Finally, the heterogeneity of fibroblast populations has been described in multiple studies, and subsets that promote or restrain carcinogenesis have been identified.85 Strategies to target fibroblasts are likely to make an impact on pancreatic cancer, considering that fibroblasts are a key mediator of immune suppression in this disease86 and that activation of an immune response represents the best chance at achieving long-term survival.87 Cancer Stem Cells: Cancer Cells MEN2B With a Survival Advantage Until now, we have been focused on cellular plasticity as it relates to normal cells in the process of neoplastic transformation. However, the plasticity also pertains to malignancy cells, especially in the context of developing effective treatments for pancreatic cancer and overcoming resistance. This is most evident in the evolution of the CSC hypothesis. The concept of CSCs or TICs stems from the notion that a populace of tumor cells survived the therapeutic regimen and remained dormant, only to recur as soon as the therapy was withdrawn. Even though the CSCs in several cancers have been studied for decades, their origin has remained an enigma. The earlier studies found that cancer cells within a tumor existed in different phenotypic says that had different functional elements. Among this heterogeneity, the CSCs formed a distinct populace of cells that had activated self-renewal pathways, tumor initiation capability, and were responsible for tumor recurrence.88,89 These cells also showed an increased tendency to metastasize and were typically resistant to therapy. Additional studies by Kreso et al90 also indicated that this populace of cells were able to reversibly transition between stem and non-stem says as well. These observationsalong with the studies that showed that microenvironmental niches like hypoxia, extracellular matrix surrounding the tumor cells, and the inflammatory milieu, can provide cues for the dynamic interconversion between CSC and non-CSCcomplicated the understanding of CSCs. Before the concept of niche influencing the enrichment or origin of CSC populace, 2 models decided the origin of CSCs. In the hierarchical model, the CSCs are considered to represent a distinct subset within the tumor that arises when a stem cell escapes regulation and gives rise to an aberrant counterpart with unrestrained self-renewal potential. This populace can not only self-renew but also differentiate into a short-lived progeny with restricted proliferative capability.91,92 This indicated that in a clinical setting, eradication of the CSCs would prevent recurrence of the tumor. The stochastic model, however, stated that every cell within a tumor was likely to be a cell of origin that can promote tumor initiation and progression. It also stated that this heterogeneity within the tumor was determined by intrinsic factors like accumulation of genetic mutations.93 These 2 apparently dichotomous models for CSCs can be explained by the CSC plasticity in the presence of the microenvironmental stimuli. This indicated that low oxygen tension, cytotoxic drugs, and oxidative.