My laboratory focuses on the biology of lung squamous cell carcinoma (LUSC), a frequent type of lung cancer that typically grows in the bronchi and exhibits a dismal prognosis and limited therapeutic options. Complex genetic landscapes, a lack of actionable therapeutic targets, and extensive inter-patient heterogeneity have delayed the development of new therapeutic and prevention strategies to reduce deaths from LUSC.
The development of patient-relevant and tractable models of LUSC is also significantly underdeveloped when compared with other lung cancers and other tumours of similar frequency. This limitation, together with the complexities that are inherent to LUSC biology, are the causes of the lack of advances in LUSC medicine.
To develop these much-needed LUSC models, we implemented a new strategy to model LUSC based on the genetic manipulation of human bronchial epithelial cells (HBECs) and bronchial organotypic cultures to target the most frequently dysregulated pathways in LUSC (Figure 1), namely the squamous differentiation (SOX2 overexpression), Nrf2 (KEAP1 knock-out) and PI3K/Akt (PTEN knock-out) pathways and common tumour suppressors (TP53 and CDKN2A knock-out). The phenotypic analysis of mutant HBECs showed a clear evolutionary trajectory that determines the transition from a normal epithelium into premalignant and invasive LUSC stages (Figure 2), consistent with the classical LUSC subtype.
Figure 1
Figure 1. Summary of the most relevant tumour suppressors (pink boxes) and pathways (blue boxes) involved in LUSC development, with examples of pathway components altered in LUSC and the percentage of cases with at least one alteration targeting the pathway. C. Haematoxylin-eosin-stained sections or air-liquid interface (ALI) HBEC cultures from wild-type and mutant HBECs that follow the most likely evolutionary trajectory of LUSC inferred from our results. The diagram below shows the phenotypic changes associated with this evolutionary trajectory.
Figure 2
Figure 2. Haematoxylin-eosin-stained sections of organotypic air-liquid interface (ALI) HBEC cultures from wild-type and mutant HBECs. The diagram shows the sequence of genetic alterations that most likely reflects the evolutionary trajectory of LUSC inferred from our results.
In addition, we were able to map very accurately the transcriptional response associated with each pathway and identify how they regulate key oncogenic pathways and immunomodulatory factors.
This model constitutes a versatile and human-relevant platform to investigate genotype–phenotype causations, identify LUSC vulnerabilities, and access the biology of premalignant lesions.
Our laboratory is currently interested in developing the possibilities of this new model, although not limited to it, to:
- Investigate the cellular and molecular origins of LUSC molecular and histological subtypes
- Unravel the mechanisms whereby LUSC cells tolerate the otherwise toxic amplification of chromosome 3q
- Develop SOX2-centred therapies that prevent the expansion of SOX2-amplified LUSC cells and spare normal cells
- Explore the effects of the SOX2 and Nrf2 pathways on LUSC immunosuppression and immunotherapy effectiveness.