PAIR-LUNG

Lung cancer reveals a highly inter- and intra-tumor heterogeneously profile. The complex collection of bidirectional interactions between the cells and the microenvironment in which they are compartmentalized plays a central role in tumor aggressiveness. Recently, the clinical and research community have widely discussed the importance of tumor spread through air spaces (STAS) concept as a pattern of invasion in pulmonary cancer. STAS phenomenon is defined as “micropapillary clusters, solid nests, or single cells spreading within air spaces beyond the edge of the main tumor” according to the 2015 World Health Organization classification (Fig.1 – A). Until now, there are no three-dimensional in vitro models that recapitulate STAS- positive lung cancer features, and thus can validate clinical markers and predict lung cancer prognosis (Fig. 1 – B).

The in vitro recapitulation of lung cancer microenvironment is really challenging. In particular, the developed models lack on the recreation of the complex spatial organization of tumor cells and tumor microenvironment-derived cells, the native distal lung microenvironment, the extracellular matrix-relevant components, the gas-exchange phenomenon, and air spaces incorporation. Moreover, patient-derived lung cancer organoids culture systems relies on the use of Matrigel-like substrates that are highly aleatory and contains animal-derived biomolecules, offering no control over individual architecture, and limiting the size range of the fabricated construct.

Here, we propose PAIR-LUNG as a multi-disciplinary and innovative project that raises from research limitations on STAS-positive lung cancer in vitro validation (Fig. 2). Our project aims to (1) develop a 3D lung cancer in vitro model able to mimic the cellular, biophysical, and biochemical cues of the native and tumor microenvironment (Fig. 1 – C); (2) understand the pathophysiology of the STAS-positive lung cancer disease, including cell phenotype/behavior and cell- extracellular matrix crosstalk in order to implement a clinical score that includes STAS positive concept to improve treatment decisions (Fig. 1 – D); and if successful (3) engineer a reproducible, precision, and personalized drug screening platform to evaluate novel targeted oncology therapies in cancer cell models and patient samples (Fig. 1 – E).
PAIR-LUNG project combines the complementary expertise of (1) NMS (B. Mendes as PI, J. Conniot as co-PI, D. Sousa, and J. Conde) in the areas of patient-derived cancer models and heterogeneous tumor microenvironment profile platforms; (2) Thoracic Surgery Unity of CHLC-HSM (P. Calvinho and J. Reis) as renowned European clinicians experts in the treatment of lung adenocarninoma; (3) FARM-ID and NMS (J. Rasvaco) as key specialist in organic synthesis and bioconjugation technology; and (4) LASIGE/FCiências.ID (N. Garcia) and COFAC (J. Carvalho) as specialists in computer vision and deep learning.