Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin

Foster, Deshka S.; Januszyk, Michael; Delitto, Daniel; Yost, Kathryn E.; Griffin, Michelle; Guo, Jason; Guardino, Nicholas; Delitto, Andrea E.; Chinta, Malini; Burcham, Austin; Nguyen, Alan; Bauer-Rowe, Khristian E.; Titan, Ashley L.; Salhotra, Ankit; Jones, Ruth Ellen; Silva, Oscar da; Lindsay, Hunter G.; Berry, Charlotte E.; Chen, Kellen; Henn, Dominic; Mascharak, Shamik; Talbott, Heather E.; Kim, Alexia N.; Nosrati, Fatimah; Sivaraj, Dharshan; Ransom, Ryan C.; Matthews, Michael R.; Khan, Anum; Wagh, Dhananjay; Coller, John A.; Gurtner, Geoffrey C.; Wan, Derrick C.; Wapnir, Irene; Chang, Howard Y.; Norton, Jeffrey A.; Longaker, Michael T.

doi:10.1016/j.ccell.2022.09.015

Cited by 102 publications

(74 citation statements)

References 52 publications

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“…Markers of late differentiation we identified in GBM CAFs such as ACTA2 have been identified in late-stage differentiated breast CAFs, underpinning that CAFs undergo similar differentiation trajectories across cancer entities ( 28 ). We also found transcriptomic evidence within cells isolated by serial trypsinization of patient GBM of 3 CAF subtypes (steady state–like, mechanoresponsive, and immunomodulatory) conserved across multiple cancer types and species ( 29 ).…”

Section: Discussionmentioning

confidence: 65%

“…These findings are consistent with breast cancer studies ( 28 ) and suggest that ACTA2 -expressing CAFs represent a more differentiated CAF subtype across cancers. We also found gene expression patterns within serially trypsinized cells from patient GBMs consistent with 3 CAF subtypes (steady state–like, mechanoresponsive, and immunomodulatory) conserved across multiple cancer types and species ( 29 ) ( Supplemental Figure 11 and Supplemental Methods ).…”

Section: Resultsmentioning

confidence: 70%

“…To identify mediators of CAF effects on GSCs, we created a resource of inferred crosstalk by mapping the expression of GSC receptors to that of their cognate ligands/agonists expressed by CAF cells, using RNA-Seq results from GBM CAFs ( Figure 1C ) and GBM6-derived neurospheres ( 37 ) ( Figure 3E and Supplemental Table 3 ). In identifying candidates from this GSC-CAF receptor-ligand analysis ( Supplemental Table 3 ) to investigate as mediators of CAF-mediated GSC enrichment, we chose osteopontin (OPN) and its receptor CD44 and hepatocyte growth factor (HGF) and its receptor c-Met because OPN and HGF are expressed by mechanoresponsive and immunomodulatory CAF subtypes ( 29 ), respectively, which we identified in cells isolated in serial trypsinization of patient GBMs ( Supplemental Figure 11 ), and because both enrich GSCs ( 38 , 39 ). We conducted a neurosphere formation assay in the presence of anti-OPN and/or anti-HGF neutralizing antibodies.…”

Section: Resultsmentioning

confidence: 99%

“…Then, to investigate potential mediators of these GSC effects on CAFs, we created the converse of our map between CAF ligands/agonists and GSC receptors ( Figure 3E ) by mapping the expression of receptors expressed by CAFs to that of their cognate ligands/agonists expressed by GSCs, using the RNA-Seq results described above ( Figure 4D and Supplemental Table 3 ). Using this resource, to investigate mediators enabling GSCs to recruit CAFs and stimulate their proliferation, we focused on PDGF and TGF-β, since both appeared in our GSC CAF ligand-receptor analysis ( Figure 4D and Supplemental Table 3 ) and both have receptor signaling in the mechanoresponsive CAF subtype ( 29 ) we identified in our cells cultured via serial trypsinization of patient GBMs ( Supplemental Figure 10 ). Varying concentrations of neutralizing antibodies to TGF-β or PDGF were placed in GSC CM before the Boyden chamber and CAFs were applied.…”

Section: Resultsmentioning

confidence: 99%

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Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects

Jain¹,

Rick²,

Joshi³

et al. 2023

Journal of Clinical Investigation

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Cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of glioblastoma specimens yielded cells with CAF morphology and single-cell transcriptomic profiles based on their lack of copy number variations (CNVs) and elevated individual cell CAF probability scores derived from the expression of 9 CAF markers and absence of 5 markers from non-CAF stromal cells sharing features with CAFs. Cells without CNVs and with high CAF probability scores were identified in single-cell RNA-Seq of 12 patient glioblastomas. Pseudotime reconstruction revealed that immature CAFs evolved into subtypes, with mature CAFs expressing actin alpha 2, smooth muscle ( ACTA2 ). Spatial transcriptomics from 16 patient glioblastomas confirmed CAF proximity to mesenchymal glioblastoma stem cells (GSCs), endothelial cells, and M2 macrophages. CAFs were chemotactically attracted to GSCs, and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF and TGF-β as mediators of GSC effects on CAFs and osteopontin and HGF as mediators of CAF-induced GSC enrichment. CAFs induced M2 macrophage polarization by producing the extra domain A (EDA) fibronectin variant that binds macrophage TLR4. Supplementing GSC-derived xenografts with CAFs enhanced in vivo tumor growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.

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Section: Discussionmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects

Jain¹,

Rick²,

Joshi³

et al. 2023

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, in a mouse model of breast cancer, mechanoresponsive (MR) CAFs may exhibit a lower differentiation state relative to immunomodulatory (IM) CAFs. By assessing the epigenomic changes of CAFs in tumors, this study suggests that the level of chromatin opening in different clusters may partly determine heterogeneity [26].…”

Section: The Heterogeneity and Subpopulation Types Of Cafsmentioning

confidence: 95%

Roles of cancer-associated fibroblasts (CAFs) in anti- PD-1/PD-L1 immunotherapy for solid cancers

Pei

Liu

et al. 2023

Mol Cancer

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In recent years, breakthroughs have been made in tumor immunotherapy. However, tumor immunotherapy, particularly anti-PD-1/PD-L1 immune checkpoint inhibitors, is effective in only a small percentage of patients in solid cancer. How to improve the efficiency of cancer immunotherapy is an urgent problem to be solved. As we all know, the state of the tumor microenvironment (TME) is an essential factor affecting the effectiveness of tumor immunotherapy, and the cancer-associated fibroblasts (CAFs) in TME have attracted much attention in recent years. As one of the main components of TME, CAFs interact with cancer cells and immune cells by secreting cytokines and vesicles, participating in ECM remodeling, and finally affecting the immune response process. With the in-depth study of CAFs heterogeneity, new strategies are provided for finding targets of combination immunotherapy and predicting immune efficacy. In this review, we focus on the role of CAFs in the solid cancer immune microenvironment, and then further elaborate on the potential mechanisms and pathways of CAFs influencing anti-PD-1/PD-L1 immunotherapy. In addition, we summarize the potential clinical application value of CAFs-related targets and markers in solid cancers.

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Understanding and measuring mechanical signals in the tumor stroma

de la Jara Ortiz,

Cimmino,

Ventre

et al. 2024

FEBS Open Bio

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The tumor microenvironment (TME) is well known for its immune suppressive role, especially in solid tumors which are characterized by a thick, dense stroma. Apart from cell–cell interactions and biochemical signals, the tumor stroma is also characterized by its distinct mechanical properties, which are dictated by the composition and architecture of its extracellular matrix (ECM). Cancer‐associated fibroblasts (CAFs) are the main producers and remodelers of the stromal ECM, and their heterogeneity has recently become a focus of intense research. This review describes recent findings highlighting CAF subtypes and their specific functions, as well as the development of 3D models to study tumor stroma mechanics in vitro. Finally, we discuss the quantitative techniques used to measure tissue mechanical properties at different scales. Given the diagnostic and prognostic value of stroma stiffness and composition, and the recent development of anti‐tumor therapeutic strategies targeting the stroma, understanding and measuring tumor stroma mechanical properties has never been more timely or relevant.

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Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin

Cited by 102 publications

References 52 publications

Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects

Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects

Roles of cancer-associated fibroblasts (CAFs) in anti- PD-1/PD-L1 immunotherapy for solid cancers

Understanding and measuring mechanical signals in the tumor stroma

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