Significance
Pancreatic adenosquamous carcinoma (ASC) is a rare but aggressive tumor, with higher metastatic potential and an even worse prognosis than pancreatic adenocarcinoma[1, 2]. A major hindrance towards development of therapies against pancreatic ASC is that the molecular mechanisms underlying its pathogenesis remain poorly characterized. In this proposal I will take advantage of the expertise on RNA biochemistry and molecular biology that I have acquired during my doctoral training and combine it with the in vivo approaches developed by the Ventura lab to investigate the potential role of non-sense mediated decay and of the UPF1 gene in pancreatic ASC.
Background
At the core of this grant proposal is the recent discovery that 78.2% …show more content…
To maximize the likelihood our findings are relevant to pancreatic cancer, I will collaborate with Dr. William Jarnagin’s group in the Pancreatic Center at MSKCC to examine whether the identified genes are deregulated in human patients with pancreatic ASC. To elucidate whether the shortlisted candidates have oncogenic potential, I will overexpress candidates in pancreatic cell lines and examine for increased cell proliferation and ability to transform primary cells. As a proof-of-concept that inhibiting these candidates can block pancreatic ASC progression, I will knockout selected candidates using CRISPR-Cas9 system and analyze for either increased apoptosis or reduced cellular proliferation in patient cell lines generated from pancreatic …show more content…
To determine whether Upf1 mutants cooperate with p53-/- and KrasG12D mutants to develop pancreatic ASC, I will cross Upf1 mutant mice with KrasG12D [10] and p53 null mice. Survival curves, tumor incidence, and tumor types arising in mice with or without Upf1 mutations will be compared. In summary, results of these studies will uncover the detailed molecular mechanism of a rare and lethal form of pancreatic cancer about which little is known today. Further, positive outcomes from these experiments could identify novel biomarkers for pancreatic ASC and potentially new drugs for
Pancreatic adenosquamous carcinoma (ASC) is a rare but aggressive tumor, with higher metastatic potential and an even worse prognosis than pancreatic adenocarcinoma[1, 2]. A major hindrance towards development of therapies against pancreatic ASC is that the molecular mechanisms underlying its pathogenesis remain poorly characterized. In this proposal I will take advantage of the expertise on RNA biochemistry and molecular biology that I have acquired during my doctoral training and combine it with the in vivo approaches developed by the Ventura lab to investigate the potential role of non-sense mediated decay and of the UPF1 gene in pancreatic ASC.
Background
At the core of this grant proposal is the recent discovery that 78.2% …show more content…
To maximize the likelihood our findings are relevant to pancreatic cancer, I will collaborate with Dr. William Jarnagin’s group in the Pancreatic Center at MSKCC to examine whether the identified genes are deregulated in human patients with pancreatic ASC. To elucidate whether the shortlisted candidates have oncogenic potential, I will overexpress candidates in pancreatic cell lines and examine for increased cell proliferation and ability to transform primary cells. As a proof-of-concept that inhibiting these candidates can block pancreatic ASC progression, I will knockout selected candidates using CRISPR-Cas9 system and analyze for either increased apoptosis or reduced cellular proliferation in patient cell lines generated from pancreatic …show more content…
To determine whether Upf1 mutants cooperate with p53-/- and KrasG12D mutants to develop pancreatic ASC, I will cross Upf1 mutant mice with KrasG12D [10] and p53 null mice. Survival curves, tumor incidence, and tumor types arising in mice with or without Upf1 mutations will be compared. In summary, results of these studies will uncover the detailed molecular mechanism of a rare and lethal form of pancreatic cancer about which little is known today. Further, positive outcomes from these experiments could identify novel biomarkers for pancreatic ASC and potentially new drugs for