Related Experiment Video

Updated: May 25, 2026

In Vivo Immunogenicity Screening of Tumor-Derived Extracellular Vesicles by Flow Cytometry of Splenic T Cells
08:02

In Vivo Immunogenicity Screening of Tumor-Derived Extracellular Vesicles by Flow Cytometry of Splenic T Cells

Published on: September 23, 2021

A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death

Abhishek D Garg1, Dmitri V Krysko, Tom Verfaillie

  • 1Cell Death Research and Therapy Unit, Department of Cellular and Molecular Medicine KU Leuven, KU Leuven, Leuven, Belgium.

The EMBO Journal
|January 19, 2012
PubMed

Insights

Cancer cells treated with photodynamic therapy (PDT) release damage-associated molecular patterns (DAMPs), including surface calreticulin and secreted ATP, to trigger anti-tumor immunity via a novel pathway involving PERK and PI3K signaling.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Surface-exposed calreticulin (ecto-CRT) and secreted ATP are critical damage-associated molecular patterns (DAMPs) that promote immunogenic apoptosis.
  • While ecto-CRT induction is linked to endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), the mechanism of ATP secretion remains unclear.

Purpose of the Study:

  • To elucidate the pathway responsible for ATP secretion during immunogenic apoptosis induced by photodynamic therapy (PDT).
  • To investigate the molecular mechanisms underlying the simultaneous release of ecto-CRT and ATP in cancer cells following ROS-mediated ER stress.

Main Methods:

  • Photodynamic therapy (PDT) was used to induce ROS-mediated ER stress in cancer cells.
  • Analysis of dendritic cell maturation and function, assessment of DAMPs release (ecto-CRT, ATP), and investigation of signaling pathways (PERK, PI3K, caspase-8) and protein interactions (LRP1/CD91).
  • Genetic depletion of key pathway components (PERK, PI3K p110α, LRP1, caspase-8) to assess their role in immunogenicity.

Main Results:

  • PDT-treated cancer cells exhibited early ecto-CRT exposure and ATP secretion prior to overt apoptotic biochemical signatures.
  • These DAMPs were released through overlapping PERK-orchestrated pathways requiring a functional secretory pathway and PI3K-mediated trafficking.
  • LRP1/CD91 was identified as the docking site for ecto-CRT, and depletion of PERK, PI3K p110α, or LRP1 reduced cancer cell immunogenicity.

Conclusions:

  • A novel PERK-dependent pathway facilitates the early and simultaneous release of ecto-CRT and ATP in response to ROS-mediated ER stress.
  • This pathway involves PI3K-mediated trafficking and the LRP1/CD91 receptor, contributing to the induction of anti-tumor immune responses.
  • Caspase-8 signaling is not essential for ecto-CRT exposure in this context.

More Related Videos

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Related Concept Videos

The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and pro-apoptotic...
Overview of Cell Death01:30

Overview of Cell Death

Cell death is an essential process where the body gets rid of old or damaged cells. Cell proliferation and death need to be balanced, as an imbalance between the two may lead to cancer or autoimmune diseases.
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the 20th century...
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.
Cytotoxic T Cells-mediated Immune Response01:27

Cytotoxic T Cells-mediated Immune Response

Cytotoxic T cells are a vital component of the immune system. They have the remarkable ability to identify and target antigens on infected or abnormal cells. These antigens often originate from intracellular pathogens such as viruses or abnormal proteins cancer cells produce.
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...