Metastasis is responsible for 90% of cancer deaths from solid tumors. Despite this reality, the mechanisms of metastasis formation are relatively understudied compared to that of carcinogenesis, deregulation of cellular pathways, or treatment resistance. It stands to reason that focused studies of metastasis provide opportunities to improve survival by identifying aspects for therapeutic development. This proposal will address Provocative Question Group B-6, """"""""Given the difficulty of studying metastasis, can we develop new approaches, such as engineered tissue grafts, to investigate the biology of tumor spread?"""""""" The hypothesis of this proposal is that subclonal genetic evolution within a primary carcinoma selects for prosurvival phenotypes, and the consequence of these phenotypes is metastasis. We propose three iterative Aims to address our hypothesis. In our first aim, we will determine the extent to which subclonal evolution generates intratumoral genetic heterogeneity and metastatic subclones within the primary site. For this aim we will apply deep sequencing of primary and metastatic tissues to determine the genetic basis of metastasis, in association with computational modeling of clonal evolution. In our second aim, we will determine the extent to which subclonal evolution nonrandomly selects for specific genes or pathways during pancreatic cancer progression.
This aim will rely upon bioinformatics analyses of sequencing libraries to identify core pathways of significance in tumor progression, coupled with mechanistic studies of metastasis formation based on genes and core pathways identified using a variety of models. In our third aim, we will determine the extent to which non-genetic factors such as EMT, oncogenic stromal signaling or immune infiltration correlates with subclonal evolution in the development of metastatic subclones.
This aim will rely on unbiased expression analyses of metastatic subclones in association with high-throughput biomarker screening. The expected overall impact of this proposal will be its potential to cause a paradigm change in our understanding of the genetic basis of tumor progression and metastasis, and to identify the core pathways and functions consistently targeted by subclonal evolution. This is important to know for the ultimate goal of devising therapies that target the metastatic phenotype and that take genetic heterogeneity into account, rather than targeting of specific genes that has shown little advantage thus far.

Public Health Relevance

Pancreatic cancer is a devastating disease largely because it is diagnosed at a late stage when metastasis has already occurred. Our research has shown that once pancreatic cancers form they continue to accumulate mutations before they become metastatic. The goal of this proposal is to evaluate the relationship of these mutations to the acquisition of metastatic ability.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA179991-01
Application #
8589767
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M1))
Program Officer
Mietz, Judy
Project Start
2013-09-01
Project End
2017-06-30
Budget Start
2013-09-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$336,150
Indirect Cost
$128,650
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Poruk, Katherine E; Valero 3rd, Vicente; Saunders, Tyler et al. (2016) Circulating Tumor Cell Phenotype Predicts Recurrence and Survival in Pancreatic Adenocarcinoma. Ann Surg 264:1073-1081
Valero 3rd, Vicente; Saunders, Tyler J; He, Jin et al. (2016) Reliable Detection of Somatic Mutations in Fine Needle Aspirates of Pancreatic Cancer With Next-generation Sequencing: Implications for Surgical Management. Ann Surg 263:153-61
Aiello, Nicole M; Bajor, David L; Norgard, Robert J et al. (2016) Metastatic progression is associated with dynamic changes in the local microenvironment. Nat Commun 7:12819
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
Rodić, 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
Niknafs, Noushin; Beleva-Guthrie, Violeta; Naiman, Daniel Q et al. (2015) SubClonal Hierarchy Inference from Somatic Mutations: Automatic Reconstruction of Cancer Evolutionary Trees from Multi-region Next Generation Sequencing. PLoS Comput Biol 11:e1004416