Elucidation of Cell Fate Transitions in Lung Cancer Stem Cells

Our goal in this proposed project in the Aerodigestive Programme is to explore cell-fate transitions in a CSC model and to use the data we generate to create predictive models that capture key interactions in the system and which can help distinguish NSC and CSC by using advanced methods including newly developed 3D organoid assays from human and mouse lungs, genetic gene manipulations with CRISPR technologies, and statistical physics, which will provide unique opportunities for students to learn cancer biology with multidisciplinary approaches. In particular, we will provide our expertise in establishing patient-derived lung cancer organoids which will be valuable resource to provide insights into understanding lung tumorigenesis and patient-centred therapeutic development. We believe our proposed project is highly attractive for the group of clinicians and physicists not only to learn oncogenic cellular changes of patient-derived tumour cells in the most physiologically relevant context but also to learn clonal distributions of tumour cells during early tumorigenesis in vivo.


Project Description

Background

Current cancer research aims at discovering molecular targets that cancer cells rely on to survive, and which may therefore be utilized to kill cancer cells. However, cancer cells in tumours display considerable heterogeneity as a consequence of genetic change, environmental differences and reversible changes in cell properties [1]. Cancer stem cells (CSCs) are thought to drive this phenotypic and functional heterogeneity among cancer cells by repopulating tumorigenic cells [2]. Therefore, identification of those tumour cells that have the capacity to reconstitute a tumour should be our next step to focus on. Furthermore, identifying the molecular factors that drive the differentiation and proliferation of CSCs in a setting that mimics the lung environment could provide an attractive drug targets for chemorefractory lung tumours.

In the lung, multiple epithelial cells have been identified as stem or progenitor cells capable of self-renewal and differentiation during regeneration and injury repair [3]. Recently, these stem cell populations have also been implicated as the cell(s)-of-origin in lung cancer; basal cells, which is the stem cells capable of self-renewal and giving rise to secretory cells in trachea, have been suggested as the cell-of-origin in the oncogenic LKB1/PTEN mouse model of lung squamous cell carcinoma (SCC), and alveolar type II cells (AT2 cells), which have been proposed to have stem cell properties in the distal lung, have also been suggested as the cell-of-origin in the oncogenic Kras mouse models of lung adenocarcinoma (ADC) [4]. However, it remains unknown what are the molecular mechanisms underlying derivation of lineage specific lung cancers and cellular heterogeneity within the tumours. Extrinsic signalling factors derived from microenvironment have been emerging as the critical regulators that maintain stem cells and establish a cellular hierarchy. Thus, studying stem cells and the interactions with their niche from wild-type and oncogenic tumour models affords the comparison of normal tissue-specific stem cells initial process of transformation and tumour heterogeneity, CSCs, and niche signals that impact their cellular behaviour.

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