Baral Garima, Pfeffer Claire M, Filippelli Sara N, Doraivel Indiraa, Heil Brittany N, Gartenhaus Lauren E, Hansen Kasi, Wu Joy, Narla Goutham, Doud Emma H, Mosley Amber L, Low-Nam Shalini T, Allen-Petersen Brittany L
bioRxiv. 2025 Jul 18:2025.07.14.664742. doi: 10.1101/2025.07.14.664742.
Pancreatic cancer is highly aggressive with a five-year survival rate of just 13%. Metabolic rewiring in response to oncogenic signals plays a critical role in pancreatic ductal adenocarcinoma (PDAC) survival, tumor growth, and metastasis. These alterations make PDAC tumors dependent on anabolic metabolism for survival, highlighting a unique vulnerability that can be therapeutically exploited. However, during nutrient deprivation, PDAC cells can circumvent this vulnerability by engulfing extracellular fluids to replenish amino acids in a process called, macropinocytosis. This process can be induced downstream of oncogenic KRAS expression, a small GTPase that is almost universally mutated in PDAC patients. The inhibition of macropinocytosis reduces PDAC tumor growth, emphasizing the importance of this pathway to cancer cell survival. However, the signaling mechanisms that regulate this process remain poorly understood. Protein phosphatase 2A (PP2A) is a heterotrimeric complex that regulates a wide variety of cell signaling pathways, including KRAS, and is commonly dysregulated in human PDAC tumors. Here, we show that acute PP2A activation prevents macropinosome processing leading to cell death. Furthermore, we demonstrate that PP2A posttranslationally regulates the lipid kinase, PIKfyve, a key regulator of macropinosome-lysosome fusion. Finally, we determine that PP2A activating compounds can function synergistically with metabolic inhibitors, supporting a new therapeutic strategy in this aggressive and deadly cancer. Together, our results implicate PP2A as a critical suppressor of PDAC metabolic plasticity and highlight the use of PP2A activating compounds to prevent PDAC nutrient scavenging.
胰腺癌具有高度侵袭性，五年生存率仅为13%。响应致癌信号的代谢重编程在胰腺导管腺癌（PDAC）的存活、肿瘤生长和转移中起着关键作用。这些改变使PDAC肿瘤依赖合成代谢来维持生存，凸显了一个可用于治疗的独特弱点。然而，在营养剥夺期间，PDAC细胞可以通过一种称为巨胞饮作用的过程吞噬细胞外液以补充氨基酸，从而规避这种弱点。这个过程可在致癌性KRAS表达的下游被诱导，KRAS是一种小GTP酶，在PDAC患者中几乎普遍发生突变。抑制巨胞饮作用可减少PDAC肿瘤的生长，强调了该途径对癌细胞存活的重要性。然而，调节这一过程的信号机制仍知之甚少。蛋白磷酸酶2A（PP2A）是一种异源三聚体复合物，可调节包括KRAS在内的多种细胞信号通路，并且在人类PDAC肿瘤中通常失调。在这里，我们表明急性PP2A激活会阻止巨胞饮体的处理，导致细胞死亡。此外，我们证明PP2A在翻译后调节脂质激酶PIKfyve，PIKfyve是巨胞饮体 - 溶酶体融合的关键调节因子。最后，我们确定PP2A激活化合物可与代谢抑制剂协同发挥作用，支持在这种侵袭性致命癌症中采用新的治疗策略。总之，我们的结果表明PP2A是PDAC代谢可塑性的关键抑制因子，并强调使用PP2A激活化合物来阻止PDAC的营养清除。
