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

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.

Oncogene-induced matrix reorganization controls CD8+T cell function in the soft-tissue sarcoma microenvironment

“…Figure 3E-H). We did observe some heterogeneity in expression, potentially due to ColVI secretion by multiple cell types including macrophages (28,49) and UPS cells themselves; however, IHC analysis clearly showed that KPY tumors exhibited significantly less strong-positive (3+) and significantly more moderately positive (2+) staining than KP tumors (Figure 2B, C). We validated these findings in vitro by qRT-PCR and immunoblotting of UPS cell lines derived from multiple unique KP GEMM tumors (KP230 and SKPY42.1 cells, referred to hereafter as "KP cells").…”

“…Despite the incredible diversity of the collagen superfamily and the abundance of collagen molecules in solid tumors (21, 28), the effects of specific collagens and other matrix proteins on T cell effector function, differentiation, and anti-tumor efficacy are only beginning to be characterized. For example, using murine lung cancer models, Peng et al (75) demonstrated that extracellular collagen molecules induced CD8 + T cell exhaustion and attenuated responses to α-Pd1 checkpoint therapy.…”

“…Although the roles of specific collagen species in cancer-associated processes are ill-defined, a growing body of literature indicates that individual collagen molecules can have context-specific functions in the TME. For example, type I collagen (ColI), a fibrillar collagen that forms prototypical collagen fibers, promotes or is associated with malignant progression in some tumor settings, but has anti-tumor effects in others (22)(23)(24)(25)(26)(27)(28). These findings underscore the need to systematically interrogate the roles of individual collagen molecules, particularly with respect to their potential impacts on adaptive immunity, in specific tumor contexts.…”

On the Value of In Vitro Cell Systems for Mechanobiology from the Perspective of Yes-Associated Protein/Transcriptional Co-Activator with a PDZ-Binding Motif and Focal Adhesion Kinase and Their Involvement in Wound Healing, Cancer, Aging, and Senescence

“…In connection with the fact that a change in the biomechanical properties of the extracellular environment entails changes in the mechanobiological properties of cells, it is an established concept in the cancer field that solid tumors show a desmoplastic reaction, including the formation of a collagen-rich connective tissue matrix [ 139 ]. In combination with the cross-linking of matrix proteins, these characteristics of desmoplasia lead to an increase in matrix rigidity.…”

Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment

“…Although the roles of specific collagen species in cancerassociated processes are ill-defined, a growing body of literature indicates that they can have context-specific functions in the TME. For example, type I collagen (ColI), a "prototypical" fibrillar collagen, promotes or is associated with malignant progression in some settings but has anti-tumor effects in others (13)(14)(15)(16)(17). These findings underscore the need to systematically interrogate the roles of individual collagens in specific tumor contexts, particularly with respect to their potential impacts on adaptive immunity.…”