Metabolic Stress & the Tumor Ecosystem in Pancreatic Cancer
Metabolic Stress Rewires Tumor Cells and the Stroma to Drive Macropinocytosis
Macropinocytosis is an endocytic mechanism of fluid-phase uptake that produces large intracellular vesicles known as macropinosomes. Macropinosomes are heterogeneous in size and shape and serve to internalize large volumes of extracellular fluid along with the associated membrane. In transformed cells, macropinocytosis is stimulated by oncogenes, such as Ras. Ras proteins are small, membrane-localized GTPases that are activated in response to growth factors and they regulate a variety of outputs, including cell proliferation, survival and invasion. Gain-of-function mutations in Ras-encoding genes cause Ras proteins to be trapped in their active state, leading to the constitutive activation of downstream pathways. We have linked macropinocytic uptake in Ras-transformed cells to nutrient delivery and amino acid supply. We demonstrated that in Ras-mutated tumors, glutamine deficiency is able to dial-up macropinocytic capacity through EGFR-Pak signaling (Lee et al., 2019). Current efforts in the lab are focused on identifying new pathways that regulate this uptake mechanism. In addition to the tumor cells, we have also demonstrated that glutamine depletion in pancreatic tumors drives macropinocytosis in stromal fibroblasts, allowing their survival and tumor-promoting properties (Zhang et al., 2021).
Tumor Cells have Evolved Homeostatic Mechanisms to Maintain pH
Unlike normal tissues, tumors display a reversal of pH gradient where they maintain an alkaline intracellular pH (pHi) and a concomitant more acidic extracellular pH. Multiple aspects of tumor progression are thought to benefit from this pH gradient switch, including tumor growth, cell death evasion, and invasiveness. To maintain an alkaline pHi, tumor cells have evolved homeostatic mechanisms to clear protons from the cytoplasm. These mechanisms include ion transporters, such as sodium-hydrogen exchangers (NHEs), that act to regulate pHi through sodium-dependent proton secretion. We recently found that NHE7 plays an integral role in pancreatic cancer tumor maintenance by regulating Golgi pH and pHi (Galenkamp et al., 2020). Our findings enhance our understanding of the mechanisms that regulate pH homeostasis in tumors and suggest that the targeting of organelle acidification might represent a novel therapeutic approach for cancer. Current efforts in the lab are focused on identifying new way that cancer cells maintain their pHi.
Glutamine Metabolism in Pancreatic Cancer Progression and Therapy
Glutamine is a critical nutrient in cancer that contributes to a wide array of biosynthetic and metabolic processes. Pancreatic cancer cells rely heavily on glutamine utilization to fulfill their metabolic and biosynthetic requirements, and therefore, it is not surprising that they are exquisitely sensitive to glutamine withdrawal. Pancreatic tumors are poorly vascularized and often encounter a paucity of nutrients. Indeed, glutamine is the most depleted amino acid in these tumors and regional glutamine deficiencies can modulate adaptation mechanisms through signal transduction. We are interested in understanding how targeting glutamine might alter the biology of a pancreatic tumor and how glutamine deficiency in the tumor microenvironment might affect progression. We recently found that glutamine depletion can drive EMT and metastasis in pancreatic cancer through the transcription factor Slug (Recouvreux et al., 2020). Current efforts in the lab are focused on the adaptive mechanisms that tumors use to deal with glutamine starvation or targeting.