Context Matters: Response Heterogeneity to Collagen-Targeting Approaches in Desmoplastic Cancers

SIMPLE SUMMARY: A common feature of tumor types such as breast cancer, prostate cancer, pancreatic cancer, and soft-tissue sarcoma is the deposition of collagen-rich tissue called desmoplasia. However, efforts to control tumor growth by disrupting desmoplasia, collectively known as “collagen-targeting approaches”, have had mixed and contradictory results, sometimes even within the same cancer type. We believe that this phenomenon may be due—at least partially—to the fact that “collagen” is not a single molecule, but rather a diverse molecular family composed of 28 unique collagen types. Therefore, in this review, we discuss the diversity of collagen molecules in normal and cancer tissue, and explore how collagen heterogeneity relates to the mixed efficacy of collagen-targeting approaches for cancer therapy. ABSTRACT: The deposition of collagen-rich desmoplastic tissue is a well-documented feature of the solid tumor microenvironment (TME). However, efforts to target the desmoplastic extracellular matrix (ECM) en masse, or collagen molecules more specifically, have been met with mixed and sometimes paradoxical results. In this review, we posit that these discrepancies are due—at least in part—to the incredible diversity of the collagen superfamily. Specifically, whereas studies of “collagen-targeting” approaches frequently refer to “collagen” as a single molecule or relatively homogeneous molecular family, 28 individual collagens have been identified in mammalian tissues, each with a unique structure, supramolecular assembly pattern, tissue distribution, and/or function. Moreover, some collagen species have been shown to exert both pro- and anti-neoplastic effects in the desmoplastic TME, even within the same cancer type. Therefore, herein, we describe the diversity of the collagen family in normal tissues and highlight the context-specific roles of individual collagen molecules in desmoplastic tumors. We further discuss how this heterogeneity relates to the variable efficacy of “collagen-targeting” strategies in this setting and provide guidance for future directions in the field.