Cancer has been classically considered as a heterogeneous set of (epi)-genetic diseases where a clone with a differentiation blockage proliferates in an uncontrolled manner to give rise to a tumor. However, an increasing number of reports have highlighted the essential role of the extracellular matrix (ECM) in tumor cell functions and tumor-related processes. Disruption of ECM network, composition or organization, contribute to cancer development and metastasis and overall disease progression. A large number of matrix proteins are dysregulated during cancer process making data analysis and interpretation very complex. Most of these proteins are inter-connected and perturbation in expression level of one of the constituents can impact the network architecture. This is the challenge of the project, where a candidate approach was preferred. We chose to study type V collagen (COLV) because it has a central role as a regulator of fibril formation and many different domains essential for cell signaling. This protein, which is quantitatively poorly represented in the ECM of healthy tissues, has an aberrant deposition in several types of tumors such as ductal infiltration carcinomas, non-small cell lung cancer, colorectal cancer and pancreatic ductal adenocarcinoma. We focused on lung carcinomas, which is one of the most frequent cancer in the world and it is also the first killer in adult patients. I studied it not from the tumoral cell but from the microenviroment perspective, which is in fact the matrix that surround those malignant cells.
My research program builds on recent conceptual advances in how the physical and structural properties of the cell microenvironment contribute to tumor progression. While there is evidence that a slight increase in the hardness of the surrounding ECM perturbs tissue function, the influence of ECM topography on cancer progression remains largely unknown. Integrating molecular biology, transcription analysis, biochemistry, high-resolution imaging and mouse and cell models, the project investigated the role of COLV in tumor progression and the underlying mechanisms. This project is original and innovative for the following reasons: (1) it will comprehensively map COLV expression patterns in cancer. Central to this part of the project are two important findings: the ECM is a dynamic structure that influences tumour progression, and multiple cell types within the tumor can contribute to ECM production. It might provide the background for potential use of COLV as a biomarker and clues for understanding its function in cancer progression, helpful to clinicians. (2) Tumoral ECM topography related to the collagen V deposition. This burgeoning field of research focuses on how physical properties of ECM impact on cell behaviour during development. Investigating how disrupted ECM topography may contribute to cancer is even newer. We aimed to connect COLV overdeposition with a specific tumoral ECM topography to crucial aspects of the tumor phenotype and gene expression. (3) Upstream regulation of collagen V by hypoxia. Recent studies have established a direct link between hypoxia and the composition and the organization of the ECM. Blocking tumor hypoxia might provide a strategy to reduce COLV overdeposition and opens a possible avenue for anti-cancer therapy. I see this part of the project as a fundamental building block that will pave the way for future research to develop new therapeutic options offered to patients.
The main objective of this proposal was to decipher the mechanisms by which deregulation of COLV expression and subsequent extracellular deposition impacts cancer development. My aim was thus to provide a more complete picture of its role in tumor ECM topography, and how these changes impacts on cancer progression with a view to exploit this knowledge for cancer diagnosis and possibly in therapy. I had 3 more specific questions to address:
1. Establishment of a compilation data of COLV expression and localization in different tumor-type categories and its the cellular sources
2. Lay down the relationship beween Collagen V overdeposition and tumor ECM topography
3. What are the upstream mechanisms responsible for dysregulation of COLV expression in cancer? Does hypoxia regulate COLV overexpression in tumors in vivo?
