| First Author | Venning FA | Year | 2021 |
| Journal | J Exp Clin Cancer Res | Volume | 40 |
| Issue | 1 | Pages | 175 |
| PubMed ID | 34016130 | Mgi Jnum | J:347534 |
| Mgi Id | MGI:6727713 | Doi | 10.1186/s13046-021-01944-4 |
| Citation | Venning FA, et al. (2021) Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer. J Exp Clin Cancer Res 40(1):175 |
| abstractText | BACKGROUND: Cancer-associated fibroblasts (CAFs) comprise a heterogeneous population of stromal cells within the tumour microenvironment. CAFs exhibit both tumour-promoting and tumour-suppressing functions, making them exciting targets for improving cancer treatments. Careful isolation, identification, and characterisation of CAF heterogeneity is thus necessary for ex vivo validation and future implementation of CAF-targeted strategies in cancer. METHODS: Murine 4T1 (metastatic) and 4T07 (poorly/non-metastatic) orthotopic triple negative breast cancer tumours were collected after 7, 14, or 21 days. The tumours were analysed via flow cytometry for the simultaneous expression of six CAF markers: alpha smooth muscle actin (alphaSMA), fibroblast activation protein alpha (FAPalpha), platelet derived growth factor receptor alpha and beta (PDGFRalpha and PDGFRbeta), CD26/DPP4 and podoplanin (PDPN). All non-CAFs were excluded from the analysis using a lineage marker cocktail (CD24, CD31, CD45, CD49f, EpCAM, LYVE-1, and TER-119). In total 128 murine tumours and 12 healthy mammary fat pads were analysed. RESULTS: We have developed a multicolour flow cytometry strategy based on exclusion of non-CAFs and successfully employed this to explore the temporal heterogeneity of freshly isolated CAFs in the 4T1 and 4T07 mouse models of triple-negative breast cancer. Analysing 128 murine tumours, we identified 5-6 main CAF populations and numerous minor ones based on the analysis of alphaSMA, FAPalpha, PDGFRalpha, PDGFRbeta, CD26, and PDPN. All markers showed temporal changes with a distinct switch from primarily PDGFRalpha+ fibroblasts in healthy mammary tissue to predominantly PDGFRbeta+ CAFs in tumours. CD26+ CAFs emerged as a large novel subpopulation, only matched by FAPalpha+ CAFs in abundance. CONCLUSION: We demonstrate that multiple subpopulations of CAFs co-exist in murine triple negative breast cancer, and that the abundance and dynamics for each marker differ depending on tumour type and time. Our results form the foundation needed to isolate and characterise specific CAF populations, and ultimately provide an opportunity to therapeutically target specific CAF subpopulations. |
