Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance

Abstract

Purpose: Cancer associated fibroblasts (CAFs) are an important component of the tumor microenvironment (TME), but a systematic investigation of their molecular characteristics and clinical relevance are lacking. Here, we sought to compare CAFs across multiple cancer types to identify critical molecular pathways activated in CAF subtypes, which may contribute to clinical outcome, disease progression, and immunotherapy resistance. Experimental Design:We performed integrated analysis of CAFs from melanoma (MEL), head and neck squamous cell carcinoma (HNSC), and lung cancer (LC), and identified the molecular characteristics that are distinctly active in each CAF subtype. Gene signatures for individual CAF subtypes were identified and used to study the association of subtype abundance with clinical outcome and immunotherapy resistance. Results:We identified six CAF subtypes (pan-CAFs) shared across cancer types and uncovered the molecular characteristics and genetic pathways distinguishing them. Interestingly, these CAF subtypes express distinct immunosuppressive factors, such as CXCL12 and CXLC14, and stemcell promoting factor IL-6. Additionally, we identified novel transcriptional drivers (MEF2C, TWIST1, NR1H3, RELB, and FOXM1) key to CAF heterogeneity. Furthermore, we showed that CAF subtypes were associated with different clinical outcomes and uncovered key molecular pathways that could activate or suppress cancer progression or were involved in resistance to anti-PD1 or anti-PD-L1 immunotherapy.

Cancer-associated fibroblast infiltration in gastric cancer: the discrepancy in subtypes pathways and immunosuppression

“…5 A). Among these targets, MYH11, FN1, COL6A1 markers of CAF subpopulation determined by single-cell sequencing [ 34 ] are upregulated in high CAF group. Consistent with DEG in RNA-seq data, EMT marker CDH1 (E-cadherin) is downregulated, and TGF-beta/BMP pathway protein ACVRL1 [ 35 ] is increased.…”

“…Among these targets, MYH11, FN1, COL6A1 markers of CAF subpopulation determined by single-cell sequencing [34] What motivated us to reemphasize the importance of P13K/AKT pathway is Rictor, the core protein of mTOR2 complex who is responsible for AKT phosphorylated activation at serine 473 (Ser473) has remarkably higher expression level in high CAF samples [36]. However, mRNA expression is roughly the same implying high We examined the prognostic performance of these protein targets by survival analysis.…”

Cancer-Associated Fibroblasts Modulate Transcriptional Signatures Involved in Proliferation, Differentiation and Metastasis in Head and Neck Squamous Cell Carcinoma

“…High expression of α-SMA has been proposed as a marker for activated fibroblasts, and a higher expression of α-SMA has been shown in CAFs compared to normal fibroblasts [52]. However, during the last years, there has been published data showing different populations of CAFs with different properties and with different expression of for example α-SMA and BMP4 [53,54]. In this study, we found a higher expression of α-SMA in the HNSCC biopsies than in non-cancerous oral tissue.…”

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

“…A mouse model with a macrophage-specific Foxm1 deletion (mac Foxm1 −/− ) demonstrated decreased macrophage recruitment and migration to lung tumors and ultimately reduced the number and size of lung tumors formed [ 250 ]. In cancer-associated fibroblasts (CAFs), FOXM1 and its downstream targets are upregulated in several cancers [ 251 ] and hepatocellular carcinoma CAFs rely on FOXM1 to activate cartilage oligomeric matrix protein ( COMP ) gene expression, which eventually increases EMT, invasion, and stemness of hepatocellular carcinoma cells [ 252 ]. The recent development of mouse models that recapitulate TME observed in human ovarian cancer [ 253 , 254 ] provides a ripe opportunity to study the role of FOXM1 in the ovarian cancer TME.…”