Friday, May 2, 2025
5/2/2025
Regulation of Nutrient Stress-Induced Macropinocytosis in Pancreatic Ductal Adenocarcinoma - 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).