# Targeting Stromal Influences on BCKA Addiction in PDAC Tumors

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $534,216

## Abstract

Failure of traditional therapy in pancreatic ductal adenocarcinoma (PDAC) is due to our limited
understanding of how the tumor microenvironment (TME) can facilitate the rapid progression or recurrence
of PDAC. In PDAC, the stromal cells identified as cancer associated fibroblasts (CAFs) account for up to
90% of tumor volume. Recent studies have revealed the significance of branched chain amino acids
(BCAAs) in cancer. However, the role of stromal cells in support of BCAA metabolism in tumors is still poorly
understood. Understanding cancer-stromal ecosystem requires insight into the intersection of cancer-
associated transformations in the stroma with reprogramming of their BCAA metabolism. SMAD4 deletion is a
frequent event in PDAC. However, the metabolic role of SMAD4-deleted PDAC cells in modulating activation of
stromal cell transformation is unknown. Our proposed aims here have aimed to bridge this knowledge gap.
We propose a differential BCAA metabolism in cancer and stromal compartments of PDAC tumors and
uncover a heavy reliance of PDAC cells on CAF-secreted branched chain keto acids (BCKAs) in stromal-
rich tumors. We hypothesize that reactive stromal BCAA metabolism is altered from quiescent stroma and is
the driver for regulating PDAC cell growth by secreting BCKAs. Second, SMAD4-deleted PDAC cells induces
metabolic alterations in stromal cells. First, we will validate stromal BCKA synthesis metabolic pathway as a
lethal target in patient-derived circulating tumor cell (CTC)-organoids and patient-derived tissue slices, using
13C-based isotope tracing and genetic tools and unravel that CAF-secreted extracellular matrix (ECM) is a
source for BCKA. To understand the mechanism behind ECM degradation, we will regulate proteasomal
proteolysis of ECM in CTC-organoids and patient-derived tissue slices. Second, to elucidate SMAD4-deletion
in PDAC cells induced metabolic rewiring of CAFs we have proposed loss-of-function studies and use CTC-
organoids and tissue slices to demonstrate increased stromal-reliance of SMAD4-deleted PDAC cells on
stromal BCAT1 and elucidate temporal metabolic reprogramming in SMAD4-deleted CTC-organoids over time
course of organoid formation. Third, we will test the efficacy of targeting BCKA anabolism in CAFs with
conditional knockout mice and perform in vivo studies targeting stromal BCKA anabolic pathway using patient-
derived low-passage cell lines and the syngeneic allograft model. Importantly, we will inhibit stromal BCAT1 in
the proposed Aims using Gabapentin, Erg 240 (BCAT1 inhibitor from Ergon Pharma), ERG 245 (BCAT1/2
inhibitor from Ergon Pharma), & CRISPR targeting of BCAT1 in CAFs. Notably, our proposed aims will reveal a
novel BCAA metabolism-centric regulatory role of reactive stroma in cancers and will uncover the underlying
mode of action of this regulation. These findings can lead to novel therapeutics targeting communication
between cancer cells and their microenvironment.

## Key facts

- **NIH application ID:** 10794299
- **Project number:** 5R01CA271369-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** THEODORE S LAWRENCE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $534,216
- **Award type:** 5
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10794299

## Citation

> US National Institutes of Health, RePORTER application 10794299, Targeting Stromal Influences on BCKA Addiction in PDAC Tumors (5R01CA271369-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10794299. Licensed CC0.

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