Spatial Molecular Plasticity Underpins Lethal Morphologies in Lung Adenocarcinoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Lung adenocarcinoma (LUAD) is a common and lethal cancer.
• Clinical grading of LUAD, based on histological growth patterns, predicts patient outcomes.
• The molecular underpinnings of distinct lethal LUAD morphologies, such as solid and micropapillary patterns, remain poorly understood.

Purpose of the Study:

• To investigate the defining molecular features of solid and micropapillary growth patterns in LUAD.
• To explore the relationship between LUAD morphology, tumor biology, and mechanisms of lethality.
• To identify potential therapeutic vulnerabilities associated with specific LUAD growth patterns.

Main Methods:

• Characterization of 7 LUAD growth patterns in 51 resected tumors using NanoString GeoMx Digital Spatial Profiler (DSP).
• Validation of gene expression findings at the protein level using Akoya PhenoImager multiplex immunofluorescence (27 cases).
• Further validation at the RNA level using Tempo-Seq (432 cases) and independent GeoMx DSP (30 cases).

Main Results:

• Gene expression analyses revealed fundamentally divergent evolutionary trajectories for solid and micropapillary LUAD growth.
• Recurrent localized intratumoral plasticity was identified in both growth patterns, explaining their origins and virulence.
• Microscopically localized hypoxia was found to influence cellular survival strategies and tumor architecture, suggesting morphology-specific metastasis mechanisms.

Conclusions:

• Dramatic divergence in gene expression programs exists between highly lethal LUAD tumor growth modes.
• Localized hypoxia plays a role in establishing and maintaining LUAD tumor architecture and survival strategies.
• The findings suggest morphology-specific mechanisms of LUAD metastasis and highlight new therapeutic vulnerabilities.