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

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $466,136

## Abstract

PROJECT SUMMARY
Recent years have witnessed a growing appreciation of the role that metabolic reprogramming plays in conferring
growth and survival advantages to tumor cells. Of particular relevance to this proposal is the now widely accepted
notion that pancreatic ductal adenocarcinoma (PDAC) cells depend on macropinocytosis as an amino acid
supply route. By stimulating the uptake of extracellular protein and targeting it for lysosomal degradation, the
macropinocytosis pathway provides cancer cells with a source of protein-derived amino acids, allowing tumors
to circumvent amino acid depletion and survive nutrient stress. Glutamine is a vital nutrient to tumors as it
supports the metabolic reactions necessary to sustain tumor cell growth; however, hearty consumption by the
tumor often leads to a glutamine-depleted tumor ecosystem. Our previously funded research demonstrated that
glutamine depletion in PDAC tumors has the capacity to modulate macropinocytosis – dialing the process up or
down as required. We attributed this inducible form of macropinocytic uptake to the activation of EGFR-Pak
signaling. Interestingly, we have found that macropinocytosis is also induced by a glutamine structural analog
that broadly suppresses glutamine metabolism; however, uptake in this setting does not employ EGFR signaling.
Since the inhibition of glutamine metabolism is being actively pursued as a therapy for cancer, we set out to
decipher how glutamine mimicry might elicit macropinocytosis as an adaptive response. We performed a high-
throughput siRNA screen and identified the atypical protein kinase C (aPKC) subfamily of kinases, PKCι and
PKCζ, as the most potent regulators of uptake. This proposal is based on our preliminary data demonstrating
that knockdown of either PKCι or PKCζ not only suppresses macropinocytosis caused by glutamine analogs,
but also abrogates uptake caused by glutamine starvation, suggesting that the aPKCs are general modulators
of nutrient stress-induced macropinocytosis. Based on these data, our central hypothesis is that aPKC signaling
is integral to nutrient stress-driven macropinocytosis and that the aPKCs support metabolic stress tolerance in
PDAC tumors. We will 1) examine the molecular mechanisms underlying the role of aPKCs in nutrient stress-
driven macropinocytosis and 2) determine the functional consequences of suppressing aPKC-dependent
macropinocytosis in PDAC. This project constitutes the first evaluation of the role that the aPKCs play in the
modulation of macropinocytosis and the first to interrogate aPKC function from the perspective of glutamine
supply. Moreover, because our work will establish aPKC-dependent macropinocytosis as a critical metabolic
adaptation in response to glutamine mimetics, our findings could have tremendous impact on the development
of novel therapeutic modalities for PDAC.

## Key facts

- **NIH application ID:** 10283951
- **Project number:** 2R01CA207189-06
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** COSIMO COMMISSO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $466,136
- **Award type:** 2
- **Project period:** 2016-07-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10283951

## Citation

> US National Institutes of Health, RePORTER application 10283951, Regulation of Nutrient Stress-Induced Macropinocytosis in Pancreatic Ductal Adenocarcinoma (2R01CA207189-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10283951. Licensed CC0.

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