# Project 2: Role of lysosomal scavenging in PDAC metabolism

> **NIH NIH P01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $416,968

## Abstract

Abstract - Project 2 (Role of Lysosomal Scavenging in PDAC Metabolism) 
Kras mutation (KRAS*) is the signature genetic alteration in pancreatic ductal adenocarcinoma (PDAC) that 
our P01 team and others have demonstrated to be critical to disease genesis and maintenance. While 
inhibitors of KRAS* have proven difficult to develop, alterations in cellular metabolism have emerged as 
promising targets for therapeutic intervention. Indeed, we have discovered that a major function of KRAS* in 
tumor maintenance is to orchestrate the profound metabolic rewiring of PDAC cells, including alterations in 
glucose and glutamine utilization. Furthermore, we have broadly elucidated additional metabolic dependencies 
of KRAS* PDAC. PDAC exhibit a strikingly high level of nutrient scavenging via autophagy and 
macropinocytosis. These processes converge at the lysosome where cargo (extracellular, from 
macropinocytosis; intracellular, from autophagy) is degraded and the resulting metabolites are recycled for 
use in anabolic and bioenergetic pathways. Indeed we and others have shown that these scavenging 
processes are critical for PDAC growth and metabolic homeostasis. We have also identified a regulatory 
network responsible for induction and integration of these recycling pathways. Based on these findings, the 
goals of Project 2 are to: 1) identify the metabolic outputs of these lysosomal pathways and how they integrate 
with cellular metabolism; 2) decipher the circuits that reprogram PDAC to rely on these pathways; 3) define 
signatures predicting reliance on these pathways; and 4) identify combinatorial approaches that effectively 
target this dependency and prevent metabolic escape. Our highly integrated joint studies will explore these 
processes in cells that escape Kras* inactivation (with Project 1) and in innovative models for tumor-stroma 
interactions (with Project 3), and depend on the Cores for tissue, drug screening, therapeutics and 
computational resources. Given ongoing clinical trials with the lysosomal inhibitor, hydroxychloroquine, these 
studies can have a transformative impact on PDAC treatment. At the same time, the full translational potential 
of our work requires integrated understanding of synergies/interferences of targeting salvage pathways, 
metabolic processes, Kras* effectors, Kras* bypass mechanisms and immune cells. The need for this integrated 
view is a central rationale of the P01 program.

## Key facts

- **NIH application ID:** 9904492
- **Project number:** 5P01CA117969-15
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** NABEEL El-BARDEESY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,968
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904492

## Citation

> US National Institutes of Health, RePORTER application 9904492, Project 2: Role of lysosomal scavenging in PDAC metabolism (5P01CA117969-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9904492. Licensed CC0.

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