Innovations and mechanisms in tumor subcellular metabolism

Project Summary/Abstract
Living cells require a constant supply of nutrients that provide energy and building blocks to support
their vital activities and growth. Fluctuations in nutrient availability are inevitable. Thus, to survive, cells need to
adapt to these changes by rewiring their metabolism. Studying this metabolic adaptation in lower organisms
has revolutionized our understanding of biological systems. For example, the discovery of how prokaryotes
respond to changes in the accessibility to lactose and glucose as a carbon source led to the concept of gene
regulation after the identification of the lac operon.
In eukaryotes the evolution of subcellular organelles provided an optimal environment for biochemical
reactions to proceed. Moreover, this system allowed the eukaryotic cell to evolve additional strategies to
acquire nutrients besides passive diffusion or transport across the cell membrane. Through the endo-
lysosomal compartment, cells can scavenge nutrients from extracellular macromolecules, which provides them
with metabolic flexibility to survive various states of nutrient availability by balancing the composition of their
microenvironment with their nutrient demands.
Nutrient acquisition strategies are fully exploited by malignant cells to survive the harsh tumor
microenvironment. Pancreatic cancer, a lethal malignancy, is a paradigm of metabolic adaptation. Hypo-
vascularization of pancreatic ductal adenocarcinoma (PDAC) limits the delivery of free nutrients and oxygen to
cancer cells. To overcome nutrient scarcity, cancer and stromal cells rely on scavenging nutrients from intra-
and extracellular macromolecules via autophagy and macropinocytosis, respectively. Both pathways converge
on the lysosome, a cellular organelle that degrades macromolecules to recycle their nutrient content.
Despite their essential role in cancer, studying lysosomes in highly heterogenous tumors in vivo is
challenging because of the lack of tools that allow the functional profiling of lysosomal content during
tumorigenesis at a cell-type-specific resolution. In this proposal, I will describe our novel approach to develop
an innovative technology that allows the rapid capturing of lysosomes from specific cell types in the tumor to
profile their metabolite, lipid and protein contents to understand how lysosomes in malignant and stromal cells
mediate metabolic adaptation. We will also design a modular mouse model system that will allow the selective
interrogation of the lysosomal response to major metabolic stressors that exist in the tumor microenvironment.
Our innovative approaches combined with functional characterization of the lysosomal components
using genetic tools will result in an unprecedent subcellular and cell-type-specific understanding of tumor
metabolism. We believe that our work has the potential to revolutionize our understanding of metabolic
adaptation in mammalian systems, and to identify vulnerabilities that can be exploited as novel therapeutic
targets in pancreatic cancer.

Grant Number: 4DP2CA271386-02
NIH Institute/Center: NIH
Principal Investigator: Monther Abu-Remaileh