# CSHL-JAX Patient-Derived Models of Pancreatic Cancer as Systems for Investigating Tumor Heterogeneity

> **NIH NIH U01** · COLD SPRING HARBOR LABORATORY · 2020 · $848,343

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with a five-year survival rate of less
than 8%. These grim statistics owe, in part, to the profound resistance of PDA to current therapies. More
effective treatment strategies would offer tremendous benefit to PDA patients. Emerging evidence suggests
that epigenetic and genetic heterogeneity exist in both the neoplastic and non-neoplastic compartments of
pancreatic tumors, and that this heterogeneity may impact response to treatment. Our own studies have
identified two subpopulations of cancer-associated fibroblasts (CAFs) present within the PDA
microenvironment, a cancer-proximal population that expresses myofibroblast markers and a cancer-distal
population that expresses inflammatory markers such as the cytokine IL-6. However, the full complement of
cell populations present within the PDA tumors and the mechanisms through which each population might
impact tumor biology remain unclear. Tackling these questions requires models that accurately recapitulate
human PDA. Patient-derived xenografts (PDXs), organoid cultures, organoid-stromal co-cultures, and organoid
xenografts have emerged as “next-generation” models that better mimic the complex interactions present in
the PDA microenvironment. Yet, the extent to which each model preserves the diverse populations found in
human tumors remains unclear. To address this question, we propose to generate a series of matching
organoid and xenograft models which we will use to characterize and perturb subpopulations of neoplastic
cells and CAFs. We will generate and characterize five sets of paired organoid culture and PDX models, where
pairs are derived the same de-identified patient tumor specimens. In addition, we will develop a new model for
pancreatic cancer in which patient-derived PDA organoids are delivered to mice in situ via injection into the
main pancreatic duct, better recapitulating the developmental trajectory of human PDA than other xenograft
approaches. We will use single-cell RNA and DNA sequencing as well as barcoded organoid lines to
characterize and perturb the neoplastic and CAF populations present in our models. To study to role of IL-6 in
PDA more directly, we will use biochemical and genetic strategies to perturb CAF-mediated IL-6 signalling in
our models. Among these, we will make use of a murine model engineered to express human IL-6 as a host for
our PDA xenografts, restoring the ability for IL-6 generated in the stroma to signal to the transplanted
neoplastic cells. Ultimately, our studies will shed light on the distinct subpopulations of neoplastic cells and
CAFs present in the PDA microenvironment and help to identify which of those subpopulations function to
promote the aggressive traits characteristic of PDA tumors. The knowledge gained from our studies will
provide valuable insights into the nature of the tumor microenvironment. Such insights should inform novel
ideas for strategies to eff...

## Key facts

- **NIH application ID:** 9879723
- **Project number:** 5U01CA224013-03
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** Paul Robson
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $848,343
- **Award type:** 5
- **Project period:** 2018-03-06 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879723

## Citation

> US National Institutes of Health, RePORTER application 9879723, CSHL-JAX Patient-Derived Models of Pancreatic Cancer as Systems for Investigating Tumor Heterogeneity (5U01CA224013-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9879723. Licensed CC0.

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