Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21

Abstract

Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes, the roles they play in cancer progression, and molecular mediators of the CAF “state.” Here, we identify a novel cell surface pan-CAF marker, CD49e, and demonstrate that two distinct CAF states, distinguished by expression of fibroblast activation protein (FAP), coexist within the CD49e+ CAF compartment in high-grade serous ovarian cancers. We show for the first time that CAF state influences patient outcomes and that this is mediated by the ability of FAP-high, but not FAP-low, CAFs to aggressively promote proliferation, invasion and therapy resistance of cancer cells. Overexpression of the FAP-low–specific transcription factor TCF21 in FAP-high CAFs decreases their ability to promote invasion, chemoresistance, and in vivo tumor growth, indicating that it acts as a master regulator of the CAF state. Understanding CAF states in more detail could lead to better patient stratification and novel therapeutic strategies.

Tumor Microenvironment in Ovarian Cancer: Function and Therapeutic Strategy

“…Despite that accumulating studies have demonstrated the pro-tumor progression impact of CAFs, it is worthy of notifying that there are different subtypes of CAFs with heterogenous function status. Recently, Hussain et al (2020) found 2 CAF subsets distinguished by the FAP expression level. The FAP-high CAF subtype, instead of the FAP-low subtype, was found to aggressively enhance tumor progression and negatively influence patient outcomes, which shed light on therapeutic strategies involving CAF modulation to consider CAF status in patient selection.…”

Targeting of the Cancer-Associated Fibroblast—T-Cell Axis in Solid Malignancies

“…The presence of this iCAF subset, characterized by high expression of IL-6 and IL-8, is associated with poor prognosis in both tumor types. Similarly, in ovarian cancer the presence of an iCAF subset, represented by CD49e + FAPhigh CAFs, with high expression of IL-6 and CXCL12, is associated with dismal prognosis of patients, which is in accordance with findings in other solid malignancies [39,44]. In head and neck cancer, a PDGF-Rα+ CAF subset can be found that expresses high levels of CXCL12 [43].…”

“…Therefore, recent efforts have focused on addressing this knowledge gap of fibroblast subset phenotype and function by mapping fibroblast heterogeneity through RNA-sequencing based approaches. Various research groups have tried to provide a roadmap of the different fibroblast subsets present in solid tumors, including pancreatic, colon, ovarian, breast, lung and head and neck cancer [36,37,38,39,40,41,42,43]. Interestingly, the number of fibroblast subsets identified varies between tumor types.…”

“…Despite differences in technical approaches, multiple studies have identified a distinct CAF subset that is characterized by the high expression of pro-inflammatory cytokines, such as IL-6, Leukemia Inhibitory Factor (LIF), IL-1β, IL-11 and CXCL12 (Figure 1G). This particular fibroblast subset is detected in pancreatic, colorectal, ovarian, breast and lung cancer and is implicated in regulating the immune response, suggesting a shared biological mechanism amongst different solid malignancies [36,39,40,42,43]. Collectively, we will refer to this distinct fibroblast subset as ‘inflammatory-type cancer-associated fibroblasts (iCAFs)’ and, due to their high immunomodulatory gene expression, zoom in on this particular subset.…”

High-throughput approaches for precision medicine in high-grade serous ovarian cancer

“…3D culture more closely resembles the tumor microenvironment by restoring 3D cell–cell and cell–ECM interactions [ 186 , 187 ]. Moreover, research groups have successfully demonstrated co-culturing with patient-derived fibroblasts [ 188 ] and patient-derived mesothelial cells [ 189 ] in HGSC spheroid models to capture the influence of tumor-stromal cross talk on survival and proliferation. Provided that HGSC disseminates through the release of multicellular aggregates into the peritoneal cavity, 3D organotypic in vitro models have been developed to recapitulate significant events in metastasis and gain insights into tumor biology [ 190 ].…”