Targeting the tumour niche in EBD skin cancer: Molecular and cellular mechanisms of skin cancer expansion governed by the extracellular matrix in EBD skin cancer (Gaggioli 3)

Short lay summary

Our skin's fibroblasts secrete the materials that form a complex network of macromolecules that provide a substrate for cell migration and mechanical support. Besides this structural role, this extracellular matrix also generates signals that regulate the communication between cells. In healthy skin, there is a dynamic balance between the accumulation and degradation of those macromolecules that ensures tissue stability and preserves its physiological function. On the contrary, chronic inflammation in RDEB results in excessive production and assembly of cancer-associated proteins, in turn leading to a more rigid extracellular matrix without reciprocal degradation, a process called fibrosis. There is evidence that increased rigidity and fibrosis of the extracellular matrix, could create a permissive habitat where tumour cells can thrive, therefore contributing to their resistance to treatment.

This project seeks to understand the role played by the rigidity of the extracellular matrix secreted by tumour cells in driving squamous cell carcinoma (SCC) expansion and resistance to chemotherapeutic agents. Gaggioli and colleagues plan to use cultured epithelial cells to investigate how the inhibition of EGFR, which plays an important role in the regulation of cell growth, proliferation and differentiation, is modulated by changes in matrix stiffness. The targeting of a signalling pathway that directs the behaviour of tumours of epithelial origin is expected to prevent or delay their growth and improve the condition of patients.

Scientific summary

Patients suffering from recessive epidermolysis bullosa (RDEB) are prone to develop aggressive and metastatic skin cancers with fatal demise. Indeed, Squamous Cell Carcinoma (SCC) tumours arise at the site of long-term blistering due to the lack of collagen VII expression, which causes separation of the epidermis from dermis with a cleavage beneath the lamina densa. Analysis of RDEB human and murine skin has demonstrated the presence of pro-inflammatory molecules at the blister area, which correlates with extracellular matrix (ECM) remodelling and increased ECM stiffness rigidity. The ECM is a complex and dynamic network of macromolecules with distinctive physical, biochemical, and biomechanical properties and plays a central role in establishing the tumour niches. In pathological conditions, including epithelial cancers, loss of tissues homeostasis and chronic inflammation lead to excessive ECM remodelling. Specific cancer-associated proteins production, deposition and assembly, which result in enhanced mechanical stiffness properties of the ECM, characterize the tumour ECM. Taken together, increased ECM accumulation without reciprocal balanced degradation lead to tissues fibrosis, which has been linked to elevated cancer aggressiveness and poor survival of patients. In return, adhesion of tumour cells to the stiff ECM results in activation of multiple signalling pathways that favour cancer cell proliferation, survival, migration and chemotherapeutic resistance. Surgery is a standard treatment for cutaneous SCC in EBD patients (EB-SCC) but is frequently limited by the anatomical extent of the tumour. Chemotherapy in cutaneous SCC treatment has evolved from palliative to a central component of the therapeutic programs for advanced disease. Cisplatin is regarded as a standard agent in combination with radiation. EGFR-TKI, gefitinib (IRESSA) or erlotinib, have shown moderate benefit on clinical outcome when given alone. In RDEB-SCC patients, conventional chemotherapy or EGFR targeted therapies are considered to be of interest in advance EB SCCs. However, EB SCCs sensitivity and the role of the ECM in non-targeted or targeted (EGFR) chemotherapies response are undefined. This research project aims at deciphering the molecular cues that in EB SCCs are triggered by the tumour niche and drive neoplastic expansion and chemotherapeutic resistance.

Strategic relevance

The resistance of cSCC to treatment with chemotherapeutic agents has been associated before with a stiffer extracellular matrix and an altered expression profile of proteins but never been demonstrated in RDEB SCC cells, hence the novelty of this study. This approach is relevant because it focuses on the contribution of the tumour microenvironment to cancer growth and expansion. Furthermore, it plans to test molecules that are already in clinical use, which if successful, could accelerate its clinical translation.