Executive Summary : | Pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive malignancy having a high mortality rate, poor prognosis, and overall 5-year survival less than 7%. Despite the availability of multi-modal therapeutic options, the median patient survival of locally advanced cancer is about 6 months, and all targeted treatment strategies remain largely ineffective due to high chemoresistance rate or early metastasis. In addition, Cancer stem cells (CsCs), are small subset of tumor cells which evade primitive PDAC treatment options such as radiation and chemotherapy, thereby mediates cell survival, and re-initiates tumor proliferation leading to recurrence and metastasis. Existence of the genetic heterogeneity and immense complexity of PDAC in available treatment response favors enhanced resistance mechanisms leading to greater morbidity and mortality rates. Thus, evaluation of novel targeted therapies are in high demand towards improving PDAC treatment efficacy and patient outcomes. In search of a novel therapeutic target for PDAC, this study will focus on key oncogenic drivers such as Yes associated protein-1 (YAP1), KRAs, MYC and RELA. several studies have highlighted the profound importance of dysregulated transcription factors such as YAP1, KRAs, MYC and RELA in PDAC tumor progression favoring tumor cell proliferation, EMT, metastasis, metabolic reprogramming, and CsC maintenance and propagation. Also, studies on miRNA-based therapeutics in PDAC showed a successful promising approach by targeting multiple oncogenic signaling networks within the cells. Thus, developing a new miRNA-based therapeutics for targeting multiple oncogenic drivers, thereby attenuating CsC self-renewal ability and propagation could yield a better therapeutic regimens for PDAC with less adverse effects in patients. Initial, in silico analysis showed elevated gene expression of key oncogenic drivers of PDAC such as YAP1, KRAs and RELA when compared to normal pancreas. Also, KM survival plot in patients showed poor survival with increased expression of YAP1, KRAs and RELA. Further, using miRDB-miRNA target prediction database, a novel miR-3154 being the common miRNA found to target key oncogenic genes such as YAP1, KRAs, MYC, and RELA responsible for driving PDAC tumorigenesis. Based upon these observations, the central hypothesis of this proposal is that miR-3154, a tumor suppressor gene attenuates PDAC through inhibiting CsCs propagation by targeting YAP1, KRAs, MYC and RELA. In this study, stable inducible miR-3154 expressing PDAC cells will be utilized to delineate the tumor suppressive role of miR-3154 (in vitro and in vivo studies) and expatiating its deleterious effects on CsCs upon expression restoration. Thus, this study unveils its significance in identifying a potential tumor suppressor miRNA-3154, and targeting key altered signaling pathways mediated by the transcription factors such as YAP1, KRAs, MYC and RELA in PDAC tumor progression and metastasis. |