Syndecan 1 Mediates Macropinocytosis in Pancreatic Cancer

Inhibition of oncogenic KRAS signaling has been proposed as a therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC), but additional strategies must be developed to minimize KRAS-independent disease recurrence. Interactions between KRAS and cell-surface proteins drive oncogenic signaling in tumorigenesis, suggesting that the function and composition of the cell-surface protein repertoire (referred to as the surfaceome) may be exploited to disrupt KRAS signaling in PDAC. Yao and colleagues utilized a doxycycline-regulated mouse model of PDAC in which Kras^G12D expression could be induced and then extinguished to characterize oncogenic KRAS–driven changes in cell-surface proteins. Mass spectrometry and an in vivo loss-of-function screen identified syndecan 1 (SDC1) among the most significantly enriched surfaceome proteins modulated by oncogenic KRAS. Surface expression of SDC1 increased and decreased following oncogenic KRAS expression and extinction, respectively. Depletion or genetic deletion of SDC1 in cells expressing oncogenic KRAS impaired colony-forming ability in vitro and inhibited the growth and progression of both mouse and human PDAC cells in vivo. In addition, Sdc1 deficiency in a mouse model of KRAS-driven PDAC extended survival, decreased tumor-cell proliferation and aggressive phenotypes, and reduced distal metastasis compared to wild-type mice. Inactivation of oncogenic KRAS blocked SDC1 recycling to the plasma membrane. Mechanistically, this dysregulation of SDC1 trafficking was due to reduced expression of the guanine nucleotide exchange factor PSD4 following oncogenic KRAS extinction, resulting in decreased activity of the small GTPase ARF6. Depletion of SDC1 in oncogenic KRAS–expressing PDAC cells inactivated RAC1 and suppressed macropinocytosis, a nutrient salvage pathway essential to sustain KRAS-driven PDAC growth. Taken together, these findings identify a cell-surface KRAS effector critical for the induction of macropinocytosis and suggest SDC1 as a potential therapeutic target in PDAC.

Yao W, Rose JL, Wang W, Seth S, Jiang H, Taguchi A, et al. Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. Nature 2019 Mar 27 [Epub ahead of print].

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