# Platelet PI3Kbeta regulation of metastasis

> **NIH NIH F30** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $51,752

## Abstract

Abstract
Metastasis is the primary cause of morbidity and mortality among patients with solid tumors. Platelets interact
with tumor cells upon their entry into the vasculature and promote the metastatic spread of these cells by several
mechanisms. Circulating tumor cells (CTCs) directly bind to and activate platelets resulting in the formation of
platelet-fibrin complexes that envelope circulating tumor cells and protect them from immune clearance.
Adhesion to tumor cells also induces the release of platelet cytokines and other soluble factors that promote
epithelial-mesenchymal transition in the tumor cells. Finally, platelets promote the adhesion of CTCs to the
endothelium, assisting in their extravasation at distant metastatic sites.
Platelet activation, adhesion, and in vivo thrombus formation require the activity of the Class IA PI 3-kinase
PI3Kb. This isoform of PI3K produces the majority of PIP3 in platelets, suggesting that PI3Kb has a unique role
in classical platelet activation. However, the role of PI3Kb in platelet-mediated cancer metastasis has yet to be
defined. We propose that PI3Kb is required for platelet activation upon interaction with tumor cells, and thereby
contributes to platelet-stimulated tumor metastasis. Aim 1 will test the role of platelet PI3Kb in platelet-stimulated
tumor cell Matrigel invasion, transendothelial migration, epithelial-mesenchymal transition, cell stemness, NFkB
activation, and platelet TGFb secretion. We will also use RNAseq and antibody arrays to more broadly examine
the role of PI3Kb in platelet chemokine/cytokine release and in transcriptional responses by tumor cells. We will
use both platelets from mice expressing mutant PI3Kb and human platelets pre-treated with the irreversible pan-
PI3K inhibitor wortmannin. Aim 2 will directly evaluate the role of platelet PI3Kb in cancer metastasis in wild type
and whole-animal or platelet-specific mutant PI3Kb mice. Murine mammary carcinoma cells will be injected
intravenously to analyze in vivo tumor cell-platelet complex formation as well as tumor cell interactions with other
leukocytes. We will also test the role of PI3Kb in tumor cell-induced thrombocytopenia and experimental
metastasis.
Isoform selective PI3Kb inhibitors were originally developed to be used as anti-thrombotic agents, as they
prevent thrombotic occlusion of injured arteries without increasing bleeding. More recently these inhibitors have
also been explored as anti-cancer agents in the treatment of PTEN-deficient cancers. This proposal seeks to
understand the potential for a broader application of these agents in cancer patients to inhibit platelet activity
and prevent metastasis in a variety of cancer types.

## Key facts

- **NIH application ID:** 10437636
- **Project number:** 5F30CA265236-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Ryan C Graff
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437636

## Citation

> US National Institutes of Health, RePORTER application 10437636, Platelet PI3Kbeta regulation of metastasis (5F30CA265236-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10437636. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*