# Adipocyte regulation of tumor survival in metastatic prostate cancer: new targets for therapy

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $411,377

## Abstract

ABSTRACT:
Bone is a favored organ for the secondary growth from prostate cancer (PCa). Metastatic PCa is lethal and the
mechanisms that drive its progression in the skeleton and contribute to the evasion of therapy are not
understood. It has been recognized that interplay of PCa cells with the bone microenvironment is one of the key
factors responsible for the adaptive pro-survival signaling in the metastatic tumor. Our own preliminary data
show that in the fat cell-rich environments such as bone marrow, bi-directional cross-talk between metastatic
tumor cells and fat cells results in key metabolic changes in both cell types, ultimately affecting tumor growth,
survival and response to therapy. The key consequences of this cancer cell-initiated paracrine crosstalk are 1)
altered oligomerization and activity of pyruvate kinase M2 (PKM2); 2) enhanced transcription of interleukin 1b
(IL-1b) ; and 3) tumor survival-promoting changes in the mitochondrial iron metabolism. Our central
hypothesis is that: tumor cell-adipocyte interactions enhance metastatic progression, while simultaneously
reducing response to current treatments, by co-opting enzymatic and transcriptional activities of PKM2 and
IL1b-mediated regulation of iron metabolism.
We propose a multi-faceted approach that includes mouse models of lipolysis, 3D culture techniques, patient
samples and PDX models, as well as state-of-the-art proteomics and RNAseq approaches to examine previously
unexplored mechanisms linking lipolysis with PKM2/IL1β-mediated survival. We will perform these studies in
three Aims. In Aim 1 we will conditionally delete adipocyte triglyceride lipase (ATGL) in adipocytes and study the
molecular mechanisms of lipolysis on tumor progression in bone and response to docetaxel. In Aim 2 we will
focus on lipid-mediated effects on PKM2 oligomerization. We will use proteomics approaches to map S-acylation
sites on PKM2 and determine how this lipid modification regulates protein kinase activity and the
phosphoproteome of the tumor to support growth and progression. In Aim 3 we will examine transcriptional
targets of PKM2/IL-1b axis and its role in regulation of mitochondrial iron metabolism in PCa cells upon
adipocyte exposure. Together, these aims provide independently valuable and novel information into the
biology of bone marrow adipose tissue and its functional role in regulating the bone tumor microenvironment
and metastatic progression. Our work will reveal new mechanisms of tumor adaptation and survival in bone
and identify novel, mechanistic targets for therapy.

## Key facts

- **NIH application ID:** 10033239
- **Project number:** 1R01CA251394-01
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Izabela Podgorski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,377
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033239

## Citation

> US National Institutes of Health, RePORTER application 10033239, Adipocyte regulation of tumor survival in metastatic prostate cancer: new targets for therapy (1R01CA251394-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10033239. Licensed CC0.

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