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Updated: Jun 17, 2025

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INPP4B promotes PDAC aggressiveness via PIKfyve and TRPML-1-mediated lysosomal exocytosis

Golam T Saffi1, Lydia To1, Nicholas Kleine1

  • 1Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.

The Journal of Cell Biology
|August 9, 2024
PubMed

Insights

Overexpression of INPP4B in pancreatic cancer cells promotes invasion by enhancing lysosomal exocytosis. This study reveals a new pathway involving INPP4B, PIKfyve, and TRPML-1 in pancreatic ductal adenocarcinoma progression.

Area of Science:

  • Molecular Oncology
  • Cell Biology
  • Cancer Progression

Background:

  • Aggressive solid tumors, including pancreatic ductal adenocarcinoma (PDAC), utilize lysosomal exocytosis to alter the tumor microenvironment, increase motility, and promote invasiveness.
  • The precise molecular mechanisms by which malignant cells co-opt lysosomal functions are not fully understood.

Purpose of the Study:

  • To investigate the role of inositol polyphosphate 4-phosphatase, Type II (INPP4B) in pancreatic ductal adenocarcinoma (PDAC) progression.
  • To elucidate the molecular pathways linking INPP4B overexpression to enhanced PDAC cell migration and invasion.

Main Methods:

  • Assessed INPP4B expression in PDAC tissues and correlated it with disease progression.
  • Investigated the effects of INPP4B overexpression on lysosomal exocytosis, cell migration, and invasion.
  • Utilized molecular biology techniques to examine the roles of PIKfyve and TRPML-1 in INPP4B-mediated signaling.

Main Results:

  • INPP4B overexpression was found to be associated with PDAC progression.
  • INPP4B overexpression enhanced peripheral lysosomal dispersion and exocytosis, leading to increased PDAC cell migration and invasion.
  • Mechanistically, INPP4B overexpression induced PtdIns(3,5)P2 generation on lysosomes via PIKfyve, which in turn activated TRPML-1 to release calcium ions (Ca2+).

Conclusions:

  • INPP4B overexpression plays a significant role in promoting the migratory and invasive properties of PDAC cells.
  • A novel oncogenic signaling axis involving INPP4B, PIKfyve, and TRPML-1 regulates lysosomal phosphoinositide homeostasis, contributing to PDAC progression.
  • These findings provide a molecular basis for the prognostic significance of INPP4B in PDAC.

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