# Elucidating Kras-driven immune infiltration and function in pancreatic cancer

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $37,318

## Abstract

Project Title: Elucidating Kras-driven immune infiltration and function in pancreatic cancer
 Pancreatic Ductal Adenocarcinoma (PDA) is a lethal malignancy with a 5-year survival rate of 9%. PDA
is characterized by a dense stroma with a heterogeneous population of fibroblasts and infiltrating immune cells.
The cross-talk between tumor cells, fibroblasts, and immune cells leads to a highly immunosuppressive
microenvironment. However, the mechanisms underlying the cross-talk is poorly understood. Mutations in the
Kras oncogene are the main drivers of PDA and are found in more than 90% of human pancreatic tumor samples.
Kras activates different downstream signaling pathways, including MAPK, PI3K/AKT and JAK/STAT signaling.
My preliminary data shows that Kras modulates the immune cells recruitment and function. The goal of this
proposal is to identify the downstream signaling pathways used by oncogenic Kras-expressing epithelial cells to
polarize macrophages to an immunosuppressive phenotype. Further, preliminary data that I generated shows
that the JAK/STAT signaling pathway is active in the stroma, while MAPK and PI3K are predominantly epithelial.
Specifically, macrophages have active JAK/STAT signaling pathway. Thus, I will investigate the role of
JAK/STAT3 signaling pathway in driving immunosuppression in macrophages. I hypothesize that oncogenic
Kras (Kras*) expression in tumor cells drives immunosuppression and that targeting JAK/STAT pathway
in macrophages will lead to reversion of the immunosuppressive phenotype aiding in the treatment of
pancreatic cancer. To study the three Kras* downstream signaling pathways and how they are involved in
macrophage polarization I will use an in vitro co-culture of tumor cells and bone marrow-derived macrophages.
I will use shRNA to downregulate expression of the main component of each pathway in tumor cells and dissect
the crosstalk using protein and RNA analysis. To understand the role of JAK/STAT in the polarization of myeloid
cells and consequently in tumor growth, I will use a genetically engineered mouse model that depletes STAT3
specifically in myeloid cells, specially macrophages. These studies will provide a comprehensive view on how
Kras* regulates the tumor microenvironment.

## Key facts

- **NIH application ID:** 10207446
- **Project number:** 5F31CA247037-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ashley Velez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,318
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-06-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207446

## Citation

> US National Institutes of Health, RePORTER application 10207446, Elucidating Kras-driven immune infiltration and function in pancreatic cancer (5F31CA247037-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10207446. Licensed CC0.

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