# Regulation of Nutrient Stress-Induced Macropinocytosis in Pancreatic Ductal Adenocarcinoma

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $195,000

## Abstract

PROJECT SUMMARY
The world has been shocked by the recent COVID-19 pandemic. Macropinocytosis is a form of endocytosis that
viruses use to gain entry into cells or to facilitate infection. Our laboratory has the most extensive experience in
investigating macropinocytosis in the context of cancer, where it functions as a nutrient acquisition pathway2-12.
Macropinocytosis is unique among other endocytic pathways because it is preceded by plasma membrane
activity in the form of ruffling. When ruffles fuse with each other they form a macropinosome that encapsulates
the surrounding fluid and associated particles. Viruses can use macropinocytosis for cellular internalization or
they can hijack macropinocytosis for other aspects of infection. Severe acute respiratory syndrome
coronaviruses (SARS-CoVs) induce macropinocytosis late in infection that is continuous, independent from cell
entry, and associated with increased infection in vitro. These viruses use their Spike protein to signal through
the epidermal growth factor receptor (EGFR) to stimulate macropinocytosis, and inhibitors of macropinocytosis
or EGFR lead to a reduction in viral spread. While CoVs do not seem to utilize macropinocytosis for entry into
the cell, they do use later steps in the macropinosome maturation pathway to augment infection. The maturation
of the macropinosome is not very well characterized, but there are some indications that specific signaling
pathways are involved. We have extensively studied EGFR-driven macropinocytosis in cancer cells and we can
use this expertise to determine strategies for blocking macropinosome maturation and SARS-CoV-2 infection.
Our hypothesis is that SARS-CoV-2 uses mature macropinosomes as a way to spread to surrounding cells,
either by inducing `macropinosome bursting' as occurs in a process called methuosis, or by traveling
extracellularly via recycling macropinosomes. In this proposal, we will explore this hypothesis by 1) taking a
candidate approache to blocking macropinosome maturation and 2) determine the mechanism of SARS-CoV-2
viral escape that involves macropinocytosis. This project will be of great significance and impact because, by
and large, a detailed picture of what controls macropinosome maturation in the context of EGFR signaling and
SARS-CoV-2 is lacking. Moreover, it will constitute the first evaluation of the impact that candidate inhibitors
have on macropinosome maturation. Understanding the regulators of macropinosome maturation will shed light
on a critical aspect of CoV biology and could lead to new approaches for the treatment of COVID-19.

## Key facts

- **NIH application ID:** 10148164
- **Project number:** 3R01CA207189-05S1
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** COSIMO COMMISSO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,000
- **Award type:** 3
- **Project period:** 2016-07-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148164

## Citation

> US National Institutes of Health, RePORTER application 10148164, Regulation of Nutrient Stress-Induced Macropinocytosis in Pancreatic Ductal Adenocarcinoma (3R01CA207189-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10148164. Licensed CC0.

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