Pancreatic cancer metastases harbor evidence of polyclonality

Ravikanth Maddipati, Ben Z. Stanger

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Studies of the cancer genome have demonstrated that tumors are composed of multiple subclones with varied genetic and phenotypic properties. However, little is known about how metastases arise and evolve from these subclones. To understand the cellular dynamics that drive metastasis, we used multicolor lineage-tracing technology in an autochthonous mouse model of pancreatic cancer. Here, we report that precursor lesions exhibit significant clonal heterogeneity but that this diversity decreases during premalignant progression. Furthermore, we present evidence that a significant fraction of metastases are polyclonally seeded by distinct tumor subclones. Finally, we show that clonality during metastatic growth—leading to either monoclonal or polyclonal expansion—differs based on the site of metastatic invasion. These results provide an unprecedented window into the cellular dynamics of tumor evolution and suggest that heterotypic interactions between tumor subpopulations contribute to metastatic progression in native tumors. SIGNIFICANCE: Studies of tumor heterogeneity indicate that distinct tumor subclones interact during cancer progression. Here, we demonstrate by lineage tracing that metastases often involve seeding by more than one clone and that subsequent cellular outgrowth depends on the metastatic site. These findings provide insight into clonal diversity and evolution in metastatic disease.

Original languageEnglish (US)
Pages (from-to)1086-1097
Number of pages12
JournalCancer discovery
Volume5
Issue number10
DOIs
StatePublished - Oct 2015
Externally publishedYes

Fingerprint

Pancreatic Neoplasms
Neoplasm Metastasis
Neoplasms
Clonal Evolution
Clone Cells
Genome
Technology

ASJC Scopus subject areas

  • Oncology

Cite this

Pancreatic cancer metastases harbor evidence of polyclonality. / Maddipati, Ravikanth; Stanger, Ben Z.

In: Cancer discovery, Vol. 5, No. 10, 10.2015, p. 1086-1097.

Research output: Contribution to journalArticle

Maddipati, Ravikanth ; Stanger, Ben Z. / Pancreatic cancer metastases harbor evidence of polyclonality. In: Cancer discovery. 2015 ; Vol. 5, No. 10. pp. 1086-1097.
@article{0a41cef4a9014fb08f397e21defcdc7e,
title = "Pancreatic cancer metastases harbor evidence of polyclonality",
abstract = "Studies of the cancer genome have demonstrated that tumors are composed of multiple subclones with varied genetic and phenotypic properties. However, little is known about how metastases arise and evolve from these subclones. To understand the cellular dynamics that drive metastasis, we used multicolor lineage-tracing technology in an autochthonous mouse model of pancreatic cancer. Here, we report that precursor lesions exhibit significant clonal heterogeneity but that this diversity decreases during premalignant progression. Furthermore, we present evidence that a significant fraction of metastases are polyclonally seeded by distinct tumor subclones. Finally, we show that clonality during metastatic growth—leading to either monoclonal or polyclonal expansion—differs based on the site of metastatic invasion. These results provide an unprecedented window into the cellular dynamics of tumor evolution and suggest that heterotypic interactions between tumor subpopulations contribute to metastatic progression in native tumors. SIGNIFICANCE: Studies of tumor heterogeneity indicate that distinct tumor subclones interact during cancer progression. Here, we demonstrate by lineage tracing that metastases often involve seeding by more than one clone and that subsequent cellular outgrowth depends on the metastatic site. These findings provide insight into clonal diversity and evolution in metastatic disease.",
author = "Ravikanth Maddipati and Stanger, {Ben Z.}",
year = "2015",
month = "10",
doi = "10.1158/2159-8290.CD-15-0120",
language = "English (US)",
volume = "5",
pages = "1086--1097",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - Pancreatic cancer metastases harbor evidence of polyclonality

AU - Maddipati, Ravikanth

AU - Stanger, Ben Z.

PY - 2015/10

Y1 - 2015/10

N2 - Studies of the cancer genome have demonstrated that tumors are composed of multiple subclones with varied genetic and phenotypic properties. However, little is known about how metastases arise and evolve from these subclones. To understand the cellular dynamics that drive metastasis, we used multicolor lineage-tracing technology in an autochthonous mouse model of pancreatic cancer. Here, we report that precursor lesions exhibit significant clonal heterogeneity but that this diversity decreases during premalignant progression. Furthermore, we present evidence that a significant fraction of metastases are polyclonally seeded by distinct tumor subclones. Finally, we show that clonality during metastatic growth—leading to either monoclonal or polyclonal expansion—differs based on the site of metastatic invasion. These results provide an unprecedented window into the cellular dynamics of tumor evolution and suggest that heterotypic interactions between tumor subpopulations contribute to metastatic progression in native tumors. SIGNIFICANCE: Studies of tumor heterogeneity indicate that distinct tumor subclones interact during cancer progression. Here, we demonstrate by lineage tracing that metastases often involve seeding by more than one clone and that subsequent cellular outgrowth depends on the metastatic site. These findings provide insight into clonal diversity and evolution in metastatic disease.

AB - Studies of the cancer genome have demonstrated that tumors are composed of multiple subclones with varied genetic and phenotypic properties. However, little is known about how metastases arise and evolve from these subclones. To understand the cellular dynamics that drive metastasis, we used multicolor lineage-tracing technology in an autochthonous mouse model of pancreatic cancer. Here, we report that precursor lesions exhibit significant clonal heterogeneity but that this diversity decreases during premalignant progression. Furthermore, we present evidence that a significant fraction of metastases are polyclonally seeded by distinct tumor subclones. Finally, we show that clonality during metastatic growth—leading to either monoclonal or polyclonal expansion—differs based on the site of metastatic invasion. These results provide an unprecedented window into the cellular dynamics of tumor evolution and suggest that heterotypic interactions between tumor subpopulations contribute to metastatic progression in native tumors. SIGNIFICANCE: Studies of tumor heterogeneity indicate that distinct tumor subclones interact during cancer progression. Here, we demonstrate by lineage tracing that metastases often involve seeding by more than one clone and that subsequent cellular outgrowth depends on the metastatic site. These findings provide insight into clonal diversity and evolution in metastatic disease.

UR - http://www.scopus.com/inward/record.url?scp=84943327727&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943327727&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-15-0120

DO - 10.1158/2159-8290.CD-15-0120

M3 - Article

C2 - 26209539

AN - SCOPUS:84943327727

VL - 5

SP - 1086

EP - 1097

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 10

ER -