# In situ mapping of activated PDGFRβ defines a prognostic discrepancy between histological subtypes of NSCLC

## TL;DR

A new method to measure PDGFRβ activation in lung cancer reveals different prognostic outcomes between cancer types.

## Contribution

Development of functional assays to detect PDGFRβ activation in situ, revealing subtype-specific prognostic differences.

## Key findings

- PDGFRβ activation correlates with expression but shows nuanced receptor status in lung cancer tissue.
- Higher PDGFRβ activation is linked to increased recurrence risk in squamous cell carcinoma, not adenocarcinoma.
- Activation is associated with a specific stromal profile enriched for LRRC15- and FAP-positive cells.

## Abstract

Increased stromal Platelet-derived growth factor receptor beta (PDGFRβ) expression is a hallmark of the desmoplastic tissue reaction in cancer and marks subsets of cancer-associated fibroblasts, pericytes, and smooth muscle cells. However, its functional status in situ has been anticipated from static expression measures, which cannot determine whether high receptor abundance reflects active signaling.

We established two second-generation proximity ligation assays (PLAs) to quantify PDGFRβ activation in the in situ environment of human lung cancer by detecting either phosphorylated PDGFRβ or its interaction with the adaptor protein Grb2. The immunofluorescence-based assays were applied to tissue-microarrays including diagnostic samples from over 600 non-small cell lung cancer (NSCLC) patients.

In lung cancer tissue, activation scores correlated with PDGFRβ expression but revealed a more nuanced receptor status, indicating variable activation despite similar expression levels. Higher PDGFRβ activation was associated with increased recurrence risk exclusively in squamous cell carcinoma, a finding not captured by conventional immunohistochemistry. This activation was accompanied by a specific stromal profile enriched for LRRC15- and FAP-positive cells, a pattern absent in adenocarcinomas.

PDGFRβ activation status provides functional information beyond receptor expression, uncovering clinically relevant, otherwise overlooked, stromal phenotypes. The approach illustrates the diagnostic potential of functional protein assays in the era of precision medicine.

The online version contains supplementary material available at 10.1186/s12964-026-02651-3.