Discovery of New Targets to Control Metastasis in Pancreatic Cancer by Single-cell Transcriptomics Analysis of Circulating Tumor Cells. Academic Article uri icon

Overview

abstract

  • Metastasis development is the leading cause of cancer-related mortality in pancreatic ductal adenocarcinoma (PDAC) and yet, few preclinical systems to recapitulate its full spreading process are available. Thus, modeling of tumor progression to metastasis is urgently needed. In this work, we describe the generation of highly metastatic PDAC patient-derived xenograft (PDX) mouse models and subsequent single-cell RNA-sequencing (RNA-seq) of circulating tumor cells (CTC), isolated by human HLA sorting, to identify altered signaling and metabolic pathways, as well as potential therapeutic targets. The mouse models developed liver and lung metastasis with a high reproducibility rate. Isolated CTCs were highly tumorigenic, had metastatic potential, and single-cell RNA-seq showed that their expression profiles clustered separately from those of their matched primary and metastatic tumors and were characterized by low expression of cell-cycle and extracellular matrix-associated genes. CTC transcriptomics identified survivin (BIRC5), a key regulator of mitosis and apoptosis, as one of the highest upregulated genes during metastatic spread. Pharmacologic inhibition of survivin with YM155 or survivin knockdown promoted cell death in organoid models as well as anoikis, suggesting that survivin facilitates cancer cell survival in circulation. Treatment of metastatic PDX models with YM155 alone and in combination with chemotherapy hindered the metastatic development resulting in improved survival. Metastatic PDX mouse model development allowed the identification of survivin as a promising therapeutic target to prevent the metastatic dissemination in PDAC.

publication date

  • June 4, 2020

Research

keywords

  • Biomarkers, Tumor
  • Liver Neoplasms
  • Lung Neoplasms
  • Neoplastic Cells, Circulating
  • Pancreatic Neoplasms
  • Single-Cell Analysis
  • Transcriptome

Identity

Scopus Document Identifier

  • 85089166804

Digital Object Identifier (DOI)

  • 10.1158/1535-7163.MCT-19-1166

PubMed ID

  • 32499301

Additional Document Info

volume

  • 19

issue

  • 8