Type VII collagen defects cause recessive dystrophic epidermolysis bullosa (RDEB), a blistering skin disorder often accompanied by epidermal cancers. To study the role of collagen VII in these cancers, we examined Ras-driven tumorigenesis in RDEB keratinocytes. Cells devoid of collagen VII did not form tumors in mice, whereas those retaining a specific collagen VII fragment (the amino-terminal noncollagenous domain NC1) were tumorigenic. Forced NC1 expression restored tumorigenicity to collagen VII-null epidermis in a non-cell-autonomous fashion. Fibronectin-like sequences within NC1 (FNC1) promoted tumor cell invasion in a laminin 5-dependent manner and were required for tumorigenesis. Tumor-stroma interactions mediated by collagen VII thus promote neoplasia, and retention of NC1 sequences in a subset of RDEB patients may contribute to their increased susceptibility to squamous cell carcinoma.

To elucidate mechanisms of cancer progression, we generated inducible human neoplasia in 3-dimensionally intact epithelial tissue. Gene expression profiling of both epithelia and stroma at specific time points during tumor progression revealed sequential enrichment of genes mediating discrete biologic functions in each tissue compartment. A core cancer progression signature was distilled using the increased signaling specificity of downstream oncogene effectors and subjected to network modeling. Network topology predicted that tumor development depends upon specific ECM-interacting network hubs. Blockade of one such hub, the β1 integrin subunit, disrupted network gene expression and attenuated tumorigenesis in vivo. Thus, integrating network modeling and temporal gene expression analysis of inducible human neoplasia provides an approach to prioritize and characterize genes functioning in cancer progression. Significance Investigating tumor progression in patient samples is complicated by etiologic heterogeneity, genetic instability, and an overabundance of precursor lesions that fail to progress. These complexities obscure construction of a dynamic picture of progression from normal tissue to invasive cancer. Here, we generate inducible human neoplasia driven by conditionally active Ras and characterize the sequence of gene expression programs engaged in epithelial tumor tissue and adjacent stroma during carcinogenesis. We show that tumor-intrinsic gene expression can be refined by sufficient downstream oncogene effectors and apply a generalizable network modeling strategy to prioritize targets based upon local interconnectivity. This analysis highlights the importance of tumor-stroma interaction during tumorigenesis and identifies β integrin as a potential oncotherapeutic that distinguishes normal and neoplastic tissue.