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 #
5R01CA179991-04
Application #
9094473
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Fingerman, Ian M
Project Start
2013-09-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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
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
Zhong, Yi; Macgregor-Das, Anne; Saunders, Tyler et al. (2017) Mutant p53 Together with TGF? Signaling Influence Organ-Specific Hematogenous Colonization Patterns of Pancreatic Cancer. Clin Cancer Res 23:1607-1620
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
Ascierto, Maria L; Makohon-Moore, Alvin; Lipson, Evan J et al. (2017) Transcriptional Mechanisms of Resistance to Anti-PD-1 Therapy. Clin Cancer Res 23:3168-3180
Reiter, Johannes G; Makohon-Moore, Alvin P; Gerold, Jeffrey M et al. (2017) Reconstructing metastatic seeding patterns of human cancers. Nat Commun 8:14114
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
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
Makohon-Moore, Alvin; Iacobuzio-Donahue, Christine A (2016) Pancreatic cancer biology and genetics from an evolutionary perspective. Nat Rev Cancer 16:553-65
Fan, Jun; Khanin, Raya; Sakamoto, Hitomi et al. (2016) Quantification of nucleic acid quality in postmortem tissues from a cancer research autopsy program. Oncotarget 7:66906-66921

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