Pancreatic adenocarcinoma is the fourth most common cause of cancer death in the United States and usually diagnosed at an advanced state. Poor clinical outcomes could be due, at least in part, to the fact that conventional therapies are directed at tumor cells, instead of targeting the cancer stem cell population. Emerging evidence showed that the Cancer Stem Cells (CSCs) is responsible for the disease aggressiveness, metastasis, and resistance to therapy in several cancers including pancreatic cancer. It is important need to identify a cancer stem cell maintenance marker to understand the cancer stem cells and to eradicate the tumors in patients. To date, few putative cancer stem cell markers (i.e. CD44, CD24, ALDH1 and CD133) have been identified. Considerable research efforts have been directed toward the identification of specific cancer stem cell maintenance markers including those of pancreatic cancer. In search of a new marker with functional significance in pancreatic cancer CSCs, we have focused on the pancreatic differentiation 2/polymerase association factor 1 or (PD2/Paf1). Interestingly, I have demonstrated that Paf1/PD2 plays a major role in the maintenance of self-renewal by interacting with Oct3/4 in mouse embryonic stem cells. In the preliminary results I have shown overexpression of PD2/Paf1 in pancreatic CSCs and its knockdown leads to reduce CSC phenotype and drug resistance property. These findings have prompted us to analyze the contributions of PD2/Paf1 on pancreatic CSC. The proposed hypothesis of this application is that the PD2/Paf1 is overexpressed in pancreatic cancer stem cells and plays a major role in the self-renewal and drug resistance in CSCs. To test our hypothesis, I propose the following aims:
Aim #1 is to analyze the CSC population and PD2/Paf1 in genetically engineered mouse progression model of pancreatic cancer. I will analyze the CSC population along with PD2/Paf1 expression in the progression of PC. These results will answer the questions (i) whether CSC population arise in early stage? (ii) how is it involved in the progression of PC?;and (iii) what is the role of PD2/Paf1 during PC progression? Aim #2 is to investigate the role of PD2/Paf1 in clonogenic variation and lineage differentiation in pancreatic cancer stem cells. We will isolate different clonogenic CSCs by different marker and analyze the importance of PD2/Paf1 in clonogenicity. We will also analyze the lineage differentiation potential of these CSCs by matrigel differentiation assay.
Aim #3 is to understand the function and mechanism(s) of PD2/Paf1 in self-renewal and drug resistance of pancreatic CSCs. The relationship between self-renewal gene Shh and drug resistance gene MDR2 will be examined by immunoprecipitation and ChIP analysis. The main innovation and impact of the study are the identification of pancreatic cancer stem cell specific novel marker PD2/Paf1 and its role in CSC maintenance would provide critical information for the long-term goal of developing novel targeted therapy for PC-CSCs which will help to manage this lethal disease.
Cancer stem cells (CSC) are responsible for the disease aggressiveness, metastasis, and resistance to therapy and tumor recurrence in several cancers including pancreatic cancer which is one of the lethal cancers in United States. The current proposal seeks to investigate the role and mechanism of a novel molecule or pancreatic differentiation 2/polymerase association factor 1 (PD2/Paf1) in pancreatic cancer stem cells. The identification of pancreatic cancer stem cell specific marker PD2/Paf1 and its role in CSC maintenance would provide extremely important information that is critical in advancing towards the long-term goal of developing novel therapeutic strategies for pancreatic cancer. The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.
| Barkeer, Srikanth; Chugh, Seema; Batra, Surinder K et al. (2018) Glycosylation of Cancer Stem Cells: Function in Stemness, Tumorigenesis, and Metastasis. Neoplasia 20:813-825 |
| Karmakar, Saswati; Dey, Parama; Vaz, Arokia P et al. (2018) PD2/PAF1 at the Crossroads of the Cancer Network. Cancer Res 78:313-319 |
| Nimmakayala, Rama Krishna; Seshacharyulu, Parthasarathy; Lakshmanan, Imayavaramban et al. (2018) Cigarette Smoke Induces Stem Cell Features of Pancreatic Cancer Cells via PAF1. Gastroenterology 155:892-908.e6 |
| Karmakar, Saswati; Seshacharyulu, Parthasarathy; Lakshmanan, Imayavaramban et al. (2017) hPaf1/PD2 interacts with OCT3/4 to promote self-renewal of ovarian cancer stem cells. Oncotarget 8:14806-14820 |
| Karmakar, Saswati; Kaushik, Garima; Nimmakayala, Ramakrishna et al. (2017) MicroRNA regulation of K-Ras in pancreatic cancer and opportunities for therapeutic intervention. Semin Cancer Biol : |
| Lakshmanan, Imayavaramban; Salfity, Shereen; Seshacharyulu, Parthasarathy et al. (2017) MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53. Clin Cancer Res 23:3906-3917 |
| Chugh, Seema; Meza, Jane; Sheinin, Yuri M et al. (2016) Loss of N-acetylgalactosaminyltransferase 3 in poorly differentiated pancreatic cancer: augmented aggressiveness and aberrant ErbB family glycosylation. Br J Cancer 114:1376-86 |
| Lakshmanan, I; Rachagani, S; Hauke, R et al. (2016) MUC5AC interactions with integrin ?4 enhances the migration of lung cancer cells through FAK signaling. Oncogene 35:4112-21 |
| Vaz, Arokia Priyanka; Deb, Shonali; Rachagani, Satyanarayana et al. (2016) Overexpression of PD2 leads to increased tumorigenicity and metastasis in pancreatic ductal adenocarcinoma. Oncotarget 7:3317-31 |
| Seshacharyulu, Parthasarathy; Ponnusamy, Moorthy P; Rachagani, Satyanarayana et al. (2015) Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer. Oncotarget 6:5164-81 |
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