Cancer plasticity, EMT and tumour progression

This research theme focuses on understanding how epithelial tumours dynamically transition between differentiated, stem-like, and mesenchymal cellular states during tumour initiation, progression, metastasis, and resistance to therapy.

Using integrative approaches combining single-cell transcriptomics, chromatin accessibility profiling, lineage tracing, intravital imaging, proteomics, and functional genetic perturbations, these studies uncovered how tumour cells acquire plasticity and hybrid epithelial–mesenchymal transition (EMT) states in response to oncogenic mutations, inflammatory signalling, extracellular matrix remodelling, and therapeutic stress.

A major aspect of this work investigated how tumour microenvironmental cues and non-genetic regulatory programmes sustain malignant cell states, metastatic competence, and therapy resistance. These studies identified key signalling axes regulating EMT dynamics, stemness, and tumour progression, while also uncovering pharmacological vulnerabilities capable of restricting cancer plasticity.

Together, these projects reveal how tumour progression is driven not only by genetic alterations, but also by dynamic and reversible cell-state transitions regulated by the tumour ecosystem and tissue microenvironment.

Selected studies

Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis

Nature (2020)
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Using mouse models of squamous cell carcinoma and integrative transcriptomic, chromatin, and proteomic profiling, this study demonstrated that loss of FAT1 promotes hybrid epithelial–mesenchymal states associated with tumour stemness, invasiveness, and spontaneous metastasis. Mechanistically, FAT1 deletion activated a CAMK2–CD44–SRC–YAP1 axis promoting mesenchymal identity while simultaneously sustaining epithelial programmes through EZH2 inactivation and SOX2 activation.

NR2F2 controls malignant squamous cell carcinoma state by promoting stemness and invasion and repressing differentiation

Nature Cancer (2021)
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This study identified NR2F2 as a key regulator sustaining malignant tumour states in skin squamous cell carcinoma. Through gain- and loss-of-function studies combined with transcriptional profiling, the work demonstrated that NR2F2 promotes tumour stemness, epithelial–mesenchymal transition, invasion, and tumour maintenance while repressing differentiation and immune infiltration programmes.

RHOJ controls EMT-associated resistance to chemotherapy

Nature (2023)
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Using spontaneous EMT mouse models and integrative transcriptomic and proteomic analyses, this work uncovered RHOJ as a critical regulator of EMT-associated resistance to chemotherapy. RHOJ enhanced replicative stress responses and DNA damage repair programmes, enabling EMT tumour cells to survive chemotherapy-induced stress.

Pharmacological targeting of netrin-1 inhibits EMT in cancer

Nature (2023)
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This study identified netrin-1 inhibition as a pharmacological strategy capable of suppressing EMT progression in cancer. Single-cell RNA sequencing revealed multiple intermediate EMT states, while treatment with NP137 prevented tumour cells from progressing toward late EMT states and increased tumour sensitivity to chemotherapy.

The extracellular matrix dictates regional competence for tumour initiation

Nature (2023)
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Combining intravital imaging, lineage tracing, and single-cell analyses, this study demonstrated that extracellular matrix composition and tissue stiffness regulate regional susceptibility to tumour initiation. Dense collagen-rich dermal environments restricted oncogene-induced cellular reprogramming and tumour formation, revealing how tissue mechanics shape tumour competence.

Innate immunity and the NF-κB pathway control prostate stem cell plasticity, reprogramming and tumor initiation

Nature Cancer (2025)
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Using lineage tracing, single-cell RNA sequencing, chromatin accessibility profiling, and organoid systems, this study demonstrated how inflammatory signalling and NF-κB activation regulate prostate basal stem cell plasticity and lineage reprogramming during tumour initiation. The work identified inflammatory signalling pathways as critical regulators of epithelial plasticity and tumour competence.

Highlights

• Hybrid EMT states promote tumour stemness, metastasis, and tumour progression.
• Tumour plasticity is dynamically regulated by inflammatory signalling and extracellular matrix remodelling.
• EMT-associated tumour cells acquire strong resistance to chemotherapy through enhanced stress-response programmes.
• Single-cell analyses reveal multiple intermediate and reversible EMT states during tumour progression.
• Mechanical properties of the tissue microenvironment regulate susceptibility to tumour initiation.
• Pharmacological targeting of EMT-associated pathways can suppress metastatic progression and increase therapy sensitivity.

My contribution

I contributed to the computational analysis of bulk and single-cell transcriptomic datasets, chromatin accessibility profiling, EMT-state annotation, trajectory inference and regulatory network analyses associated with tumour plasticity and malignant progression. My work also involved integrating multi-omics datasets to characterise hybrid EMT states, inflammatory signalling programmes, extracellular matrix remodelling, and tumour microenvironmental interactions regulating cancer initiation, metastasis and therapy resistance.