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VPS37A loss creates CASP8-dependent vulnerability via the MAP3K7-NF-κB-CFLAR axis.

Tatsuya Hattori1,2, Longgui Chen1, Xinwen Liang1

  • 1Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.

Cancer Gene Therapy
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VPS37A downregulation in cancer creates a synthetic lethal vulnerability. Targeting the MAP3K7-NF-κB-CFLAR axis triggers apoptosis in tumors with VPS37A loss, offering a new therapeutic strategy.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • VPS37A, an ESCRT-I subunit, is crucial for endosomal sorting and autophagy.
  • VPS37A is frequently downregulated in various human cancers, often linked to chromosome 8p deletions.
  • Early downregulation of VPS37A occurs during tumorigenesis and persists throughout tumor progression.

Purpose of the Study:

  • To investigate the functional consequences of VPS37A downregulation in cancer.
  • To identify synthetic lethal interactions and therapeutic vulnerabilities associated with VPS37A loss.
  • To explore the mechanistic basis for targeting cancer cells with VPS37A deficiency.

Main Methods:

  • Integrative analysis of VPS37A gene copy number and CRISPR screening data.
  • Investigated the MAP3K7-NF-κB-CFLAR signaling axis and its role in VPS37A-deficient cells.
  • Utilized spheroid tumor models to assess therapeutic targeting efficacy.

Main Results:

  • VPS37A deficiency, often due to 8p deletion, establishes a synthetic lethal dependency on the MAP3K7-NF-κB-CFLAR axis.
  • Targeting this axis induced CASP8-mediated apoptosis and suppressed tumor growth in VPS37A-deficient models.
  • This vulnerability relies on ATG8ylated membranes for CASP8 activation, independent of receptor sorting disruption.
  • Selective apoptosis induction was observed in spheroid tumors with 8p deletion, even with co-deleted death receptors.

Conclusions:

  • VPS37A loss confers a selective vulnerability in cancer cells, particularly those with chromosome 8p deletions.
  • The MAP3K7-NF-κB-CFLAR axis represents a promising therapeutic target for cancers with VPS37A downregulation.
  • This study provides a mechanistic rationale for developing targeted therapies against VPS37A-deficient tumors.