# Multi-Omics Characterization of Lactate-Associated Molecular Subtypes in Lung Cancer Suggests a Role for DKK1 in Lactate-Linked Migration, Invasion, and Lactylation Programs

## TL;DR

This study identifies two lactate-related lung cancer subtypes with different survival outcomes and shows that DKK1 is linked to cancer spread and lactate-related changes.

## Contribution

The study introduces a lactate-based molecular subtype framework and identifies DKK1 as a novel lactate-responsive gene involved in cancer metastasis.

## Key findings

- Two lactate-associated subtypes were identified with distinct survival and immune profiles.
- DKK1 was found to promote migration and invasion in response to lactate exposure.
- Multi-omics analysis confirmed DKK1 dysregulation at both transcript and protein levels.

## Abstract

Metabolic reprogramming is a common feature of various cancers, and lactate metabolism disorder plays a crucial role in lung cancer progression. This study aims to explore the molecular subtypes related to lactate metabolism in lung cancer and the key genes involved. By integrating multi-omics data and functional experiments, we identified lactate-based subtypes with different prognostic outcomes and a lactate-related prognostic gene signature. We also found that the lactate-regulated gene Dickkopf-1 (DKK1) promotes lung cancer metastasis. These findings provide new insights for lung cancer prognosis assessment and targeted therapy.

Background: Lactate accumulation is increasingly recognized as a feature of tumor metabolic reprogramming that can coincide with immune dysregulation and aggressive phenotypes. The prognostic and immunologic relevance of lactate-associated heterogeneity in lung cancer remains to be clarified. Methods: We curated lactate-related genes and identified prognostic candidates in lung cancer cohorts. Consensus clustering was applied to define lactate-associated molecular subtypes, followed by characterization of survival and tumor microenvironment features. A LASSO-based gene signature was developed to generate an individual-level risk score and an integrated nomogram. Multi-omics analyses were used to evaluate concordance between transcriptomic and proteomic alterations. Single-cell transcriptomic data were analyzed to explore cellular heterogeneity in lactate-related programs. In vitro assays evaluated the response of candidate genes to lactate exposure and assessed cell migration and invasion under proliferation-inhibited conditions after genetic perturbation. Results: Two lactate-associated molecular subtypes were identified with distinct overall survival and divergent immune microenvironment features. Subtype 1 was associated with better outcomes and a more immune-inflamed profile, whereas Subtype 2 was associated with poorer outcomes and a myeloid-enriched, immunosuppressive contexture. Pathway analyses indicated subtype-associated differences in extracellular matrix-related processes and apoptosis-associated signaling. We developed an 11-gene prognostic signature and nomogram that stratified patients by risk across TCGA and GEO cohorts. Multi-omics integration highlighted ANLN, FGA, and DKK1 as consistently dysregulated at both transcript and protein levels. Among these candidates, DKK1 showed lactate-responsive induction in vitro. DKK1 perturbation altered lactate-enhanced migratory and invasive phenotypes and was accompanied by changes in intracellular lactate levels and global protein lactylation, supporting a potential feedforward relationship between lactate exposure, DKK1 expression, and lactylation. Conclusions: This study characterizes lactate-associated molecular heterogeneity in lung cancer and provides a lactate-related subtype framework and prognostic risk model for patient stratification. The findings nominate DKK1 as a lactate-responsive candidate linked to migration/invasion phenotypes and lactate/lactylation changes in vitro.