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Targeting Phosphatidylserine Synthesis for Tumor Cell Suppression in Esophageal Squamous Cell Carcinoma and
Yixuan Hu1,2, Yaqi Cui1,2, Zeqiong Xu1,2
1State Key Laboratory of Gene Expression, School of Life Sciences, Westlake University, Hangzhou 310030, China.
Abstract:
While altered lipid metabolism is a hallmark of cancer, specific phospholipid dependencies remain poorly defined. Here, we identify phosphatidylserine synthase 1 (PTDSS1) as a targetable metabolic vulnerability in esophageal squamous cell carcinoma (ESCC) and glioblastoma (GBM). Pharmacological inhibition of PTDSS1 selectively and potently suppresses tumor growth both in vitro and in vivo. Mechanistically, PTDSS1 blockade triggers a rapid collapse of cellular phosphatidylserine (PS) and phosphatidylethanolamine (PE) pools, fundamentally disrupting endoplasmic reticulum (ER) homeostasis. This targeted lipid depletion activates a PERK-mediated autophagic response that ultimately yields to apoptosis. Clinically, pan-cancer transcriptomic analysis links elevated PTDSS1 expression to reduced overall survival across diverse malignancies. Collectively, we establish PTDSS1 as an essential maintainer of ER integrity and highlight PS biosynthesis as a viable therapeutic target for exploiting tumor-specific metabolic dependencies.
Insights
Researchers identified phosphatidylserine synthase 1 (PTDSS1) as a key metabolic vulnerability in cancers like esophageal squamous cell carcinoma (ESCC) and glioblastoma (GBM). Inhibiting PTDSS1 halts tumor growth by disrupting cell membranes and triggering cell death, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Altered lipid metabolism is a known hallmark of cancer.
- Specific phospholipid dependencies driving cancer progression are not well understood.
Purpose of the Study:
- Identify targetable metabolic vulnerabilities in cancer.
- Investigate the role of phosphatidylserine synthase 1 (PTDSS1) in esophageal squamous cell carcinoma (ESCC) and glioblastoma (GBM).
Main Methods:
- Utilized pharmacological inhibition of PTDSS1 in vitro and in vivo.
- Analyzed cellular phosphatidylserine (PS) and phosphatidylethanolamine (PE) pools.
- Investigated endoplasmic reticulum (ER) homeostasis and PERK-mediated autophagy.
- Performed pan-cancer transcriptomic analysis.
Main Results:
- PTDSS1 inhibition selectively suppressed tumor growth in ESCC and GBM models.
- PTDSS1 blockade led to a collapse of PS and PE pools, disrupting ER homeostasis.
- This triggered PERK-mediated autophagy, ultimately resulting in apoptosis.
- Elevated PTDSS1 expression correlated with reduced overall survival across multiple cancer types.
Conclusions:
- PTDSS1 is essential for maintaining ER integrity in cancer cells.
- Targeting phosphatidylserine (PS) biosynthesis represents a viable therapeutic strategy for exploiting cancer-specific metabolic dependencies.
