Laura D. Attardi, Ph.D., Professor of Radiation Oncology and of Genetics, Stanford University School of Medicine, Co-Director Stanford Cancer Biology Graduate Program

Research Description: Pancreatic ductal adenocarcinoma (PDAC) is slated to be the 2nd leading cause of cancer deaths by 2026. PDAC, which has a 5-year survival rate of ~10%, is particularly deadly because symptoms manifest late, after the cancer has metastasized, and because treatments are largely ineffective. It is therefore imperative to better understand PDAC initiation and evolution to develop better early detection strategies and therapeutic interventions.

Dr. Attardi’s research for the past 20 years has focused on elucidating the pathways through which the p53 transcription factor acts to suppress tumorigenesis in vivo. A critical role for p53 in suppressing pancreatic cancer is underscored by the observation that p53 is mutated in approximately 75% of these cancers. A major focus is therefore to understand the mechanisms of p53 action in suppressing pancreatic cancer using integrated mouse genetic, cell biological, biochemical, and genomic approaches. In one approach, the Attardi laboratory has identified a p53 “super” tumor suppressor that suppresses pancreatic cancer better than wild-type p53 in vivo, which has helped to provide insight into the pathways through which p53 acts. In addition, the Attardi laboratory is performing CRISPR/Cas9 screens to identify p53-inducible genes critical for p53-mediated tumor suppression. Another area of interest is in identifying the cell-of-origin for pancreatic cancer and understanding how different types of p53 mutations act in this compartment to promote cancer. The Attardi lab has used tractable mouse models to activate the Kras oncogene and modulate tumor suppressor genes in either ductal or acinar cells of the pancreas to drive cancer. They have discovered that PDAC can initiate from either cell type, leading to transcriptionally distinct cancers that correlate with specific subtypes of human PDAC. They are further deconstructing paths of PDAC development by exploring the transcriptome, chromatin landscape, and tumor microenvironment through single cell RNA-sequencing and spatial transcriptomics. These approaches will elaborate the mechanisms of initiation and paths of tumor evolution in this deadly disease, helping to improve the diagnosis, prognostication, and treatment of pancreatic cancers.

Dr. Attardi has active collaborations with various members of the PCRG, including Drs. Winslow, Artandi, Jackson, Engleman, and Kim, which has greatly facilitated the laboratory’s work on p53 function in pancreatic cancer.

Selected relevant publications (Stanford PCRG members in bold):

  1. Flowers, B.M., Xu, H., Mulligan, A.S., Hanson, K.J., Seoane, J.A., Vogel, H., Curtis, C., Wood, L.D., and L.D. Attardi. (2021) Cell-of-origin influences pancreatic cancer subtype. Cancer Discovery. 11(3):660-677. PMCID: PMC8134763

  2. Bieging-Rolett, K.T., Kaiser, A., Morgens, D.W., Boutelle, A.M., Seoane, J.A., Van Nostrand, E.L., Zhu, C., Houlihan, S.L., Mello, S.S., Yee, B.A., McClendon, J., Pierce, S.E., Winters, I.P., Wang, M., Connolly, A.J., Lowe, S.W., Curtis, C., Yeo, G.W., Winslow, M.M., Bassik, M.C., and L.D. Attardi. (2020) Zmat3 is a key splicing regulator in the p53 tumor suppression program. Molecular Cell. 80(3):452-469.e9. PMCID: PMC7654708

  3. Mello, S.S., Valente, L.J., Raj, N., Seoane. J.A., Flowers, B.M., McClendon, J., Bieging-Rolett, K.T., Lee, J., Ivanochko, D., Kozak, M.M., Chang, D.T., Longacre, T.A., Koong, A.C., Arrowsmith, C.H., Kim, S.K., Vogel, H., Wood. L.D., Hruban, R.H., Curtis, C., and L.D. Attardi. (2017) A p53 super-tumor suppressor reveals a tumor suppressive p53-Ptpn14-Yap axis in pancreatic cancer. Cancer Cell. 32(4): 460-473. PMCID: PMC5659188.

  4. Mello S.S., Sinow, C., Raj, N., Mazur, P.K., Bieging-Rolett, K., Broz, D.K., Imam, J.F.C., Vogel, H., Wood, L.D., Sage, J., Hirose, T., Nakagawa. S, Rinn, J., and L.D. Attardi. (2017) Neat1 is a p53-inducible lincRNA essential for transformation suppression. Genes Dev. 31(11): 1095-1108. PMCID: PMC5538433