Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic cancer

Cell Rep. 2021 Oct 19;37(3):109852. doi: 10.1016/j.celrep.2021.109852.


Effective treatments for pancreatic ductal adenocarcinoma (PDAC) are lacking, and targeted agents have demonstrated limited efficacy. It has been speculated that a rare population of cancer stem cells (CSCs) drives growth, therapy resistance, and rapid metastatic progression in PDAC. These CSCs demonstrate high clonogenicity in vitro and tumorigenic potential in vivo. However, their relevance in established PDAC tissue has not been determined. Here, we use marker-independent stochastic clonal labeling, combined with quantitative modeling of tumor expansion, to uncover PDAC tissue growth dynamics. We find that in contrast to the CSC model, all PDAC cells display clonogenic potential in situ. Furthermore, the proximity to activated cancer-associated fibroblasts determines tumor cell clonogenicity. This means that the microenvironment is dominant in defining the clonogenic activity of PDAC cells. Indeed, manipulating the stroma by Hedgehog pathway inhibition alters the tumor growth mode, revealing that tumor-stroma crosstalk shapes tumor growth dynamics and clonal architecture.

Keywords: PDAC; cancer stem cells; lineage tracing; pancreatic cancer; stem cell dynamics; stroma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cancer-Associated Fibroblasts / metabolism
  • Cancer-Associated Fibroblasts / pathology
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Communication
  • Cell Line, Tumor
  • Cell Lineage*
  • Cell Proliferation
  • Female
  • Hedgehog Proteins / antagonists & inhibitors
  • Hedgehog Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Pyridines / pharmacology
  • Signal Transduction
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Time Factors
  • Tumor Burden
  • Tumor Microenvironment*
  • Xenograft Model Antitumor Assays


  • Anilides
  • Antineoplastic Agents
  • Hedgehog Proteins
  • HhAntag691
  • Pyridines