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CYRI-B Regulates Macropinocytic Uptake of LPAR1 to Control Metastasis in Pancreatic Cancer


Core Concepts
CYRI-B, a regulator of RAC1 and macropinocytosis, controls the internalisation of the lysophosphatidic acid receptor LPAR1, thereby modulating chemotactic migration and metastasis in pancreatic cancer.
Abstract
The content explores the role of CYRI-B, a RAC1-interacting protein, in pancreatic ductal adenocarcinoma (PDAC) progression and metastasis using the KPC mouse model. Key highlights: CYRI-B expression increases during PDAC progression in the KPC mouse model. Deletion of CYRI-B accelerates the formation of precancerous lesions (PanINs) and enhances proliferation through hyperactivation of ERK and JNK pathways downstream of RAC1. However, loss of CYRI-B reduces metastasis to the liver and bowel in the KPC model. CYRI-B localizes to macropinocytic cups and vesicles and is required for efficient internalization of the lysophosphatidic acid receptor LPAR1. CYRI-B depletion impairs chemotactic migration towards serum, which is dependent on LPAR1 internalization via macropinocytosis. The study reveals a dual role for CYRI-B in PDAC - it acts as a buffer of RAC1 hyperactivation to limit early lesion formation, but is also required for macropinocytic uptake of the metastasis-driving LPAR1 receptor. This highlights CYRI-B as a regulator of both growth and metastasis in pancreatic cancer.
Stats
CYRI-B RNA probes per mm2 increased significantly from 6 weeks to endpoint in the KPC mouse model. The median survival of CKPC mice (118 days) was significantly reduced compared to KPC mice (187 days). CKPC mice showed more PanIN2 and PanIN3 lesions at 15 weeks compared to KPC controls. The percentage of pERK and pJNK positive area was significantly higher in 15-week-old CKPC pancreata compared to KPC. The number of BrdU positive proliferating cells was significantly increased in 15-week-old CKPC pancreata compared to KPC. The incidence of liver and bowel metastasis was significantly reduced in CKPC mice compared to KPC. The number of mesenteric metastatic foci was significantly reduced in mice injected with CYRI-B knockout KPC cells compared to control.
Quotes
"CYRI-B is highly expressed in PDAC and can contribute to PDAC development, progression and metastasis." "Loss of CYRI-B accelerates PanIN formation and increases pJNK, pERK and proliferation." "CYRI-B regulates metastatic potential and is required for efficient chemotactic migration towards serum." "CYRI-B localizes on macropinocytic cups and vesicles and is required for efficient internalization of the lysophosphatidic acid receptor LPAR1."

Deeper Inquiries

How might the dual roles of CYRI-B in early lesion formation and later metastasis be therapeutically targeted in pancreatic cancer

The dual roles of CYRI-B in early lesion formation and later metastasis in pancreatic cancer present unique opportunities for therapeutic targeting. In the early stages, where CYRI-B acts as a buffer of RAC1 hyperactivation, potential therapeutic strategies could involve targeting downstream effectors of RAC1 signaling. This could include inhibitors of ERK and JNK pathways to counteract the enhanced proliferation observed in precancerous lesions due to CYRI-B loss. Additionally, targeting molecules involved in maintaining epithelial polarity, disrupted by CYRI-B depletion, could be beneficial in preventing the progression of early lesions to invasive cancer. In the context of metastasis, where CYRI-B plays a role in regulating chemotactic migration and LPAR1 trafficking, therapeutic approaches could focus on inhibiting the interaction between CYRI-B and LPAR1. Small molecules or peptides that disrupt this interaction could potentially inhibit the chemotactic responses of pancreatic cancer cells towards LPA, thereby reducing metastatic spread. Targeting the macropinocytic machinery involved in LPAR1 internalization, which is dependent on CYRI-B, could also be a viable strategy to impede metastasis in pancreatic cancer.

What other signaling pathways or cellular processes might be affected by the loss of CYRI-B-mediated macropinocytosis beyond LPAR1 trafficking

The loss of CYRI-B-mediated macropinocytosis could impact several other signaling pathways and cellular processes beyond LPAR1 trafficking. Macropinocytosis is a complex process that involves the internalization of extracellular material, including growth factors, nutrients, and receptors. Therefore, the loss of CYRI-B could affect the uptake and trafficking of various growth factor receptors, such as EGFR or PDGFR, leading to altered signaling cascades in pancreatic cancer cells. This disruption in receptor internalization could impact cell proliferation, survival, and migration, contributing to tumor progression. Furthermore, macropinocytosis is a major mechanism for nutrient scavenging in cancer cells, allowing them to acquire essential nutrients for growth and survival. The loss of CYRI-B-mediated macropinocytosis could impair the uptake of nutrients, affecting the metabolic profile of pancreatic cancer cells. This disruption in nutrient uptake could lead to metabolic stress, altered energy production, and changes in the tumor microenvironment, influencing tumor progression and response to therapy.

Could the macropinocytic uptake of other growth factor receptors or nutrient transporters also be regulated by CYRI-B, and how might this impact tumor metabolism and progression

The macropinocytic uptake of other growth factor receptors or nutrient transporters could indeed be regulated by CYRI-B, impacting tumor metabolism and progression in pancreatic cancer. Apart from LPAR1, receptors such as EGFR, PDGFR, and insulin receptors are known to undergo macropinocytic internalization in cancer cells. The loss of CYRI-B could disrupt the internalization and trafficking of these receptors, affecting downstream signaling pathways involved in cell proliferation, survival, and migration. Moreover, nutrient transporters such as amino acid transporters and glucose transporters are also internalized through macropinocytosis in cancer cells to support their metabolic demands. CYRI-B-mediated macropinocytosis could play a role in regulating the uptake of these nutrients, impacting the metabolic reprogramming of pancreatic cancer cells. Disruption of nutrient uptake through macropinocytosis could lead to metabolic alterations, affecting the growth and survival of tumor cells and influencing tumor progression.
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