The process of metastasis causes 90% of solid tumor cancer deaths, yet there is little known about the contributing factors to this deadly stage of disease. There are few treatment options available for patients who harbor metastases, especially in those patients whose metastatic disease is more advanced. More direct studies of metastasis are necessary to elucidate biological driving mechanisms, identify effective therapeutic targets and improve overall survival. Pancreatic ductal adenocarcinoma (PDAC) has an extremely low survival rate and many patients are diagnosed in the metastatic stage. The hypothesis of this proposal is that the development of lethal pancreatic cancer metastasis depends on subclonal evolution occurring within the primary tumor. This proposal has two Aims to address this hypothesis. For the first aim, the phylogenetic relationships between organ-specific metastases will be determined. Deep sequencing of all gross metastases present in four rapid autopsy patients will reveal the phylogenetic relationships of each metastasis to each other.
The second aim will determine if metastases in different target organs within the same patient originate from a single or multiple metastatic subclones from the matching primary tumor. For this aim, the deep sequencing of multiple physically distinct sections of the primary tumors of the same patients in Aim 1 will elucidate the genetic life history of each carcinoma and allow for the geographical mapping of the number and location of metastatic subclones. Thus, this study will reveal the phylogenetics and evolutionary history of metastasis in PDAC, improving the overall knowledge and therapeutic targeting of this lethal stage.
This proposal is expected to have an overall impact by potentially causing a paradigm shift in the understanding of genetic alterations underlying carcinogenesis and metastasis, and to elucidate the core phenotypes or pathways that are commonly driven by subclonal evolution. This knowledge is essential for the vital goal of creating therapies specifically targeting metastatic phenotypes rather than specific genes.
|Reiter, Johannes G; Makohon-Moore, Alvin P; Gerold, Jeffrey M et al. (2018) Minimal functional driver gene heterogeneity among untreated metastases. Science 361:1033-1037
|Makohon-Moore, Alvin P; Matsukuma, Karen; Zhang, Ming et al. (2018) Precancerous neoplastic cells can move through the pancreatic ductal system. Nature 561:201-205
|McDonald, Oliver G; Li, Xin; Saunders, Tyler et al. (2017) Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet 49:367-376
|Makohon-Moore, Alvin P; Zhang, Ming; Reiter, Johannes G et al. (2017) Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet 49:358-366
|Perry, Elizabeth B; Makohon-Moore, Alvin; Zheng, Caihong et al. (2017) Tumor diversity and evolution revealed through RADseq. Oncotarget 8:41792-41805
|Reiter, Johannes G; Makohon-Moore, Alvin P; Gerold, Jeffrey M et al. (2017) Reconstructing metastatic seeding patterns of human cancers. Nat Commun 8:14114
|Makohon-Moore, Alvin; Iacobuzio-Donahue, Christine A (2016) Pancreatic cancer biology and genetics from an evolutionary perspective. Nat Rev Cancer 16:553-65
|Rodi?, Nemanja; Steranka, Jared P; Makohon-Moore, Alvin et al. (2015) Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. Nat Med 21:1060-4
|Ewing, Adam D; Gacita, Anthony; Wood, Laura D et al. (2015) Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution. Genome Res 25:1536-45