Novel CAF-identifiers via transcriptomic analysis in oral cancer patients

Background Cancer-associated fibroblasts (CAFs), a prominent component of the tumor microenvironment, plays an important role in tumor development, invasion, and drug resistance. The expression of distinct “CAF markers,” which separates CAFs from normal fibroblasts and epithelial cells, have traditionally been used to identify them. These commonly used CAF markers have been reported to differ greatly across microenvironmental subpopulations even within a cancer site. Methods Using an unbiased data analysis approach utilizing publicly available and in-house gene expression data from patient derived novel CAF cells, we identified a collection of markers in oral cancer to distinguish CAF populations from tumor epithelia and normal oral fibroblasts. Results COL1A1, SPARC, COL1A2, COL3A1 and TIMP-1 were identified as potential markers which can be utilized to differentiate cancer associated fibroblast from all other cell types including normal fibroblasts in oral cancer.

[1]  V. Pillai,et al.  Establishment and characterization of novel autologous pair cell lines from two Indian non‑habitual tongue carcinoma patients. , 2022, Oncology reports.

[2]  V. Pillai,et al.  Establishment and characterization of novel autologous pair primary cultures from two Indian non-habitual tongue carcinoma patients , 2022, bioRxiv.

[3]  Liangsheng Fan,et al.  Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling , 2021, Frontiers in Immunology.

[4]  G. Thomas,et al.  Cancer-Associated Fibroblasts in Oral Cancer: A Current Perspective on Function and Potential for Therapeutic Targeting , 2021, Frontiers in Oral Health.

[5]  D. Zheng,et al.  Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance , 2021, Clinical Cancer Research.

[6]  Su-Hyung Hong,et al.  Cancer-Associated Fibroblast Subgroups Showing Differential Promoting Effect on HNSCC Progression , 2021, Cancers.

[7]  U. Rodeck,et al.  Cancer-Associated Fibroblast Density, Prognostic Characteristics, and Recurrence in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis , 2020, Frontiers in Oncology.

[8]  R. Yin,et al.  Biomarkers for cancer-associated fibroblasts , 2020, Biomarker research.

[9]  M. Tavassoli,et al.  Portrait of a CAF: The story of cancer-associated fibroblasts in head and neck cancer. , 2020, Oral oncology.

[10]  Uri Alon,et al.  Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome , 2020, Nature Cancer.

[11]  E. King,et al.  NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors , 2020, Cancer Research.

[12]  Shiva Kumar,et al.  Multi-omics Data Integration, Interpretation, and Its Application , 2020, Bioinformatics and biology insights.

[13]  R. Langer,et al.  Immunohistochemical analysis of the expression of cancer-associated fibroblast markers in esophageal cancer with and without neoadjuvant therapy , 2019, Virchows Archiv.

[14]  M. Tan,et al.  Collagen Induces a More Proliferative, Migratory and Chemoresistant Phenotype in Head and Neck Cancer via DDR1 , 2019, Cancers.

[15]  A. Hakimi,et al.  Tumor Microenvironment Dynamics in Clear-Cell Renal Cell Carcinoma. , 2019, Cancer discovery.

[16]  L. Galluzzi,et al.  Macrophages and Metabolism in the Tumor Microenvironment. , 2019, Cell metabolism.

[17]  D. Tuveson,et al.  IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. , 2018, Cancer discovery.

[18]  Carmit Levy,et al.  Bone marrow–derived fibroblasts are a functionally distinct stromal cell population in breast cancer , 2018, The Journal of experimental medicine.

[19]  I. Arun,et al.  A subtype of cancer-associated fibroblasts with lower expression of alpha-smooth muscle actin suppresses stemness through BMP4 in oral carcinoma , 2018, Oncogenesis.

[20]  P. Mehlen,et al.  Notch Signaling in the Tumor Microenvironment. , 2018, Cancer cell.

[21]  Inna Kuperstein,et al.  Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. , 2018, Cancer cell.

[22]  Jia Gu,et al.  fastp: an ultra-fast all-in-one FASTQ preprocessor , 2018, bioRxiv.

[23]  E. King,et al.  Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4 , 2017, Journal of the National Cancer Institute.

[24]  L. J. K. Wee,et al.  Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors , 2017, Nature Genetics.

[25]  Hans Clevers,et al.  Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer , 2017, The Journal of experimental medicine.

[26]  T. Oyama,et al.  Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages , 2016, Oncotarget.

[27]  E. King,et al.  Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis , 2016, Aging.

[28]  P. Gascard,et al.  Carcinoma-associated fibroblasts: orchestrating the composition of malignancy , 2016, Genes & development.

[29]  T. Dominko,et al.  FGF2 Overrides TGFβ1‐Driven Integrin ITGA11 Expression in Human Dermal Fibroblasts , 2016, Journal of cellular biochemistry.

[30]  Kevin W Eliceiri,et al.  A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers , 2015, Oncotarget.

[31]  I Jurisica,et al.  Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer , 2015, Oncogene.

[32]  G. Charras,et al.  Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis , 2015, EMBO reports.

[33]  Magdi H Yacoub,et al.  Expression of smooth muscle cell markers and co-activators in calcified aortic valves. , 2015, European heart journal.

[34]  Xin Zheng,et al.  TIMP-1 activated carcinoma-associated fibroblasts inhibit tumor apoptosis by activating SDF1/CXCR4 signaling in hepatocellular carcinoma , 2015, Oncotarget.

[35]  R. Sanz-Pamplona,et al.  Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs, providing prognostic information , 2014, Molecular oncology.

[36]  M. Birrer,et al.  Calcium Dependent FAK/CREB/TNNC1 Signaling Mediates the Effect of Stromal MFAP5 on Ovarian Cancer Metastatic Potential , 2014, Nature Communications.

[37]  D. Gullberg,et al.  Integrin α11β1: a major collagen receptor on fibroblastic cells. , 2014, Advances in experimental medicine and biology.

[38]  W. Oh,et al.  TIMP-1 Promotes Accumulation of Cancer Associated Fibroblasts and Cancer Progression , 2013, PloS one.

[39]  G. Thomas,et al.  Progression of genotype-specific oral cancer leads to senescence of cancer-associated fibroblasts and is mediated by oxidative stress and TGF-β. , 2013, Carcinogenesis.

[40]  S. Watson,et al.  Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC-2 , 2012, Journal of thrombosis and haemostasis : JTH.

[41]  P. Soon-Shiong,et al.  SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients. , 2009, Translational oncology.

[42]  Raghu Kalluri,et al.  The basics of epithelial-mesenchymal transition. , 2009, The Journal of clinical investigation.

[43]  Robert Axelrod,et al.  Ecological therapy for cancer: defining tumors using an ecosystem paradigm suggests new opportunities for novel cancer treatments. , 2008, Translational oncology.

[44]  M. Kojima,et al.  Podoplanin, a novel marker of tumor-initiating cells in human squamous cell carcinoma A431. , 2008, Biochemical and biophysical research communications.

[45]  Liang Xie,et al.  Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. , 2007, Cancer research.