PROMYELOCYTIC LEUKEMIA PROTEIN MAINTAINS THE SPHEROID FORMATION CAPACITY OF LUNG ADENOCARCINOMA CELLS THROUGH A RETINOIC ACID-CRABP1 AXIS
Date
2025-08-15
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Abstract
The promyelocytic leukemia (PML) protein, traditionally recognized as a tumour
suppressor, has been implicated in pro-tumorigenic roles through regulation of self
renewal capacity of cancer stem cells in several malignancies, including leukemia and
breast cancer. However, a pro-tumorigenic role for PML in lung cancer has not been
described. Using murine and human lung adenocarcinoma cell lines, and CRISPR-Cas9
PML knockout (KO) cell models we determined that loss of PML expression affected
several cell properties associated with cancer cell “stemness” including tumour sphere
formation and the downward trend of several stem cell-associated genes. In addition, we
observed an attenuated response of PML KO cells to all-trans retinoic acid (ATRA)
through a mechanism involving the down regulation of the cellular retinoic acid binding
protein 1 (CRABP1). Together, these findings indicate a potential role for PML in
maintenance of “stemness” in lung adenocarcinoma.
Description
This project investigates the role of promyelocytic leukemia (PML) protein in lung adenocarcinoma, with a focus on its influence over stem-like properties and therapeutic response. Using CRISPR-Cas9–generated knockout cell lines across multiple KRAS-driven lung cancer models, we examined how PML loss impacts tumour sphere formation, stemness-associated gene expression, and responsiveness to all-trans retinoic acid (ATRA). The presented data support a model in which PML sustains stem-like behaviour through regulation of the CRABP1–RA signalling axis, where CRABP1 downregulation following PML loss impaired RA sensitivity and reduced tumour sphere formation. Functional rescue with CRABP1 addback partially restored these phenotypes, underscoring its relevance. Although the initial analysis suggested a crosstalk between PML and the Hippo-YAP axis, subsequent results demonstrated an inconsistent pattern, indicating a context-dependent or indirect relationship. This work highlights a novel role of PML in lung adenocarcinoma through CRABP1 in KRAS-driven models.
Keywords
PML-NB, Lung cancer