Recent evidence suggests that mutations in tissue stem cells generate cancer stem cells, which initiate the formation of many epithelial malignancies. These cancer stem cells are more resistant to chemotherapy and radiation, implying that tumors with a poor prognosis, such as pancreatic ductal adenocarcinoma (PDAC), may originate from cancer stem cells. There is indeed suggestive evidence that PDAC arises from a putative stem cell compartment in the tips of the ducts (the centroacinar cells), but lack of a marker for this cell compartment has precluded direct demonstration of a ductal origin of PDAC. This gap has recently been closed with our identification of the transcription factor Sox9 as an exclusive marker of ductal and centroacinar cells in the adult pancreas. To specifically target this cell compartment, our laboratory has recently developed Sox9-CreERT2 mice that express an inducible form of Cre-recombinase in Sox9-positive cells. As activating mutations in K-ras are common early mutations in human PDAC and initiate formation of PDAC precursor lesions (PanlNs) in mice, I propose to use Sox9-CreERT2 mice to initiate K-ras activation, specifically in ductal/centroacinar cells. This will determine if PanlNs originate from the ductal/centroacinar cell compartment. Based on our recent finding that Sox9 is required for the proliferation and survival of stem/progenitor cells in the embryonic pancreas and is also highly expressed in PanlNs, my second aim will assess a possible role for Sox9 in tumor progression. I propose to test whether lentiviral shRNA-mediated Sox9 inactivation in pancreatic cancer cell lines inhibits cell proliferation and tumor growth in nude mice. I will also test whether Sox9 is required for initiation of K-ras-mediated PanIN formation. These studies will determine whether Sox9-positive ductal/centroacinar cells are the cell-of-origin for PDAC and whether Sox9 promotes tumor initiation and progression. Identification of the cellular origin of PDAC is imperative for the development of effective therapies against resistant cell populations in this highly lethal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA136124-03
Application #
7923189
Study Section
Special Emphasis Panel (ZRG1-F09-B (20))
Program Officer
Jakowlew, Sonia B
Project Start
2008-09-30
Project End
2011-09-29
Budget Start
2010-09-30
Budget End
2011-09-29
Support Year
3
Fiscal Year
2010
Total Cost
$52,154
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kopp, Janel L; Dubois, Claire L; Schaeffer, David F et al. (2018) Loss of Pten and Activation of Kras Synergistically Induce Formation of Intraductal Papillary Mucinous Neoplasia From Pancreatic Ductal Cells in Mice. Gastroenterology 154:1509-1523.e5
Fox, Raymond G; Lytle, Nikki K; Jaquish, Dawn V et al. (2016) Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature 534:407-411
Font-Burgada, Joan; Shalapour, Shabnam; Ramaswamy, Suvasini et al. (2015) Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer. Cell 162:766-79
Shih, Hung Ping; Kopp, Janel L; Sandhu, Manbir et al. (2012) A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development 139:2488-99
Kopp, Janel L; von Figura, Guido; Mayes, Erin et al. (2012) Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22:737-50
Kopp, Janel L; Dubois, Claire L; Schaffer, Ashleigh E et al. (2011) Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138:653-65
Dorrell, Craig; Erker, Laura; Schug, Jonathan et al. (2011) Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev 25:1193-203
Carpentier, Rodolphe; Suner, Regina Espanol; van Hul, Noemi et al. (2011) Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 141:1432-8, 1438.e1-4
Kopp, Janel L; Dubois, Claire L; Hao, Ergeng et al. (2011) Progenitor cell domains in the developing and adult pancreas. Cell Cycle 10:1921-7