Differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma
Open accessAbstract
Background & Aims Although the healthy pancreas consists mostly of epithelial cells, pancreatic cancer and the precursor lesions known as pancreatic intraepithelial neoplasia, are characterized by an extensive accumulation of fibroinflammatory stroma that includes a substantial and heterogeneous fibroblast population. The cellular origin of fibroblasts within the stroma has not been determined. Here, we show that the Gli1 and Hoxb6 markers label distinct fibroblast populations in the healthy mouse pancreas. We then set out to determine whether these distinct fibroblast populations expanded during carcinogenesis. Methods We developed genetically engineered models using a dual-recombinase approach that allowed us to induce pancreatic cancer formation through codon-optimized Flp recombinase-driven epithelial recombination of Kirsten rat sarcoma viral oncogene homolog while labeling Gli1 + or Hoxb6 + fibroblasts in an inducible manner. By using these models, we lineage-traced these 2 fibroblast populations during the process of carcinogenesis. Results Although in the healthy pancreas Gli1 + fibroblasts and Hoxb6 + fibroblasts are present in similar numbers, they contribute differently to the stroma in carcinogenesis. Namely, Gli1 + fibroblasts expand dramatically, whereas Hoxb6 + cells do not. Conclusions Fibroblasts present in the healthy pancreas expand during carcinogenesis, but with a different prevalence for different subtypes. Here, we compared Gli1 + and Hoxb6 + fibroblasts and found only Gli1 + expanded to contribute to the stroma during pancreatic carcinogenesis.
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Fabp4+ stellate cells give rise to a minority of CAFs.
“recent lineage tracing studies targeting Fabp4+ stellate cells revealed that they give rise to a minority of CAFs142,143”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [143]
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Lemoine, N. R. (1993) · Springer eBooks · doi:10.1007/978-3-642-77437-9_63 · Cited by 124 · see citing works
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Self-citationThe activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis
Rajurkar, M., DeJesus-Monge, W. E., Driscoll, D. R., Appleman, V. A., Huang, H., Cotton, J. L., Klimstra, D., Zhu, L., Simin, K., Xu, L., et al. (2012) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1114168109 · Cited by 119 · cited 1× · see citing works
“Gli1 has been found to be expressed in epithelial cells in a variable manner across tumor lines.(28,49) In this advanced disease progression model, we did not observe epithelial Gli1 expression.”
BackgroundCD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice
Zhang, Y., Yan, W., Mathew, E., Bednar, F., Wan, S., Collins, M. A., Evans, R. A., Welling, T. H., Vonderheide, R. H., & di Magliano, M. P. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0016-t · Cited by 102 · see citing works
Self-citationHedgehog signaling in pancreas development and disease
Lau, J., Kawahira, H., & Hebrok, M. (2006) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5357-z · Cited by 95 · see citing works
DOSAGE-DEPENDENT REGULATION OF PANCREATIC CANCER GROWTH AND ANGIOGENESIS BY HEDGEHOG SIGNALING
Mathew, E., Zhang, Y.-Q., Holtz, A., Kane, K. T., Song, J. Y., Allen, B. L., & di Magliano, M. P. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.010 · Cited by 92 · cited 1× · see citing works
“We previously described a small population of Gli1þ fibroblasts in the healthy pancreas.(27,30) In a number of other organs, tissue-resident Gli1þ cells are mesenchymal progenitors that associate closely with the vasculature until activation into proliferative myofibroblasts by injury.”
BackgroundSelf-citationTranscriptional control of subtype switching ensures adaptation and growth of pancreatic cancer
Adams, C. R., Htwe, H. H., Marsh, T., Wang, A. L., Montoya, M. L., Subbaraj, L., Tward, A. D., Bardeesy, N. M., & Perera, R. M. (2019) · eLife · doi:10.7554/elife.45313 · Cited by 87 · cited 1× · see citing works
“Gli1 has been found to be expressed in epithelial cells in a variable manner across tumor lines.(28,49) In this advanced disease progression model, we did not observe epithelial Gli1 expression.”
BackgroundCarrière, C., Young, A. L., Gunn, J. R., Longnecker, D. S., & Korc, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027725 · Cited by 77 · see citing works
Chen, K., Chen, L., Hu, Y., Ding, N., Li, Y., McGuire, T. L., Lu, H., Kessler, J. A., & Kan, L. (2017) · Bone · doi:10.1016/j.bone.2017.06.014 · Cited by 76 · cited 1× · see citing works
“All data are expressed as means ± S instances of endochondral heterotopic ossification and bone marrow fibrosis.(31,35) Gli1þ fibroblasts have not been characterized in the pancreas, and their contribution to tumor-”
MethodLau, J., & Hebrok, M. (2010) · Diabetes · doi:10.2337/db09-0914 · Cited by 59 · see citing works
Epithelial-Stromal Interactions in Pancreatic Cancer
Zhang, Y., Crawford, H. C., & di Magliano, M. P. (2018) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114515 · Cited by 47 · cited 2× · see citing works
“This fibroinflammatory environment develops during the early steps of tumorigenesis and supports tumor growth and metastasis, although the roles of the individual components are still not fully understood.(4) Fibroblasts are a prominent and active cellular component of the stroma; they contribute to the secretion of e…”
BackgroundSelf-citationMesenchymal Hox6 function is required for pancreatic endocrine cell differentiation
Larsen, B. M., Hrycaj, S., Newman, M., Li, Y., & Wellik, D. M. (2015) · Development · doi:10.1242/dev.126888 · Cited by 46 · cited 2× · see citing works
“developing pancreas, and regulates the embryonic development of the organ.(36) To assess the expression of Hoxb6 in the adult pancreas, we followed a similar strategy to that described before for Gli1.”
BackgroundSelf-citationMathew, E., Collins, M., Fernández-Barrena, M. G., Holtz, A., Yan, W., Hogan, J. O., Tata, Z., Allen, B. L., Fernández-Zapico, M., & di Magliano, M. P. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.556563 · Cited by 43 · see citing works
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Myeloid Cell-Derived HB-EGF Drives Tissue Recovery After Pancreatitis
Wen, H.-J., Gao, S., Wang, Y., Ray, M., Magnuson, M., Wright, C., di Magliano, M. P., Frankel, T., & Crawford, H. (2019) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2019.05.006 · Cited by 30 · see citing works
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Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
Clinical and therapeutic relevance of cancer-associated fibroblasts
Chen, Y., McAndrews, K. M., & Kalluri, R. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00546-5 · Cited by 1,230 · see citing works
Cancer-associated fibroblasts: from basic science to anticancer therapy
Yang, D., Liu, J., Qian, H., & Zhuang, Q. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01013-0 · Cited by 572 · see citing works
Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance
Sherman, M. H., & Beatty, G. L. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-031621-024600 · Cited by 481 · see citing works
Activated fibroblasts in cancer: Perspectives and challenges
Caligiuri, G., & Tuveson, D. A. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.02.015 · Cited by 431 · see citing works
Han, L., Wu, Y., Fang, K., Sweeney, S., Roesner, U. K., Parrish, M., Patel, K., Walter, T., Piermattei, J., Trimboli, A., et al. (2023) · Nature Communications · doi:10.1038/s41467-022-34464-6 · Cited by 369 · see citing works
Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy
Barrett, R. L., & Puré, E. (2020) · eLife · doi:10.7554/elife.57243 · Cited by 351 · see citing works
“Further adding to the complexity is that fibroblasts in healthy tissue, from skin to pancreas, exhibit heterogeneity even before activation (Philippeos et al., 2018; Garcia et al., 2020).”
BackgroundInhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer
Steele, N. G., Biffi, G., Kemp, S. B., Zhang, Y., Drouillard, D., Syu, L.-J., Yuan, H., Oni, T. E., Brosnan, E., Elyada, E., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3715 · Cited by 289 · see citing works
“The healthy pancreas is home to distinct fibroblast populations (24, 25), which have differing potential to expand during carcinogenesis (26).”
BackgroundSelf-citationXiao, Z., Todd, L., Huang, L., Noguera-Ortega, E., Lu, Z., Huang, L., Kopp, M., Li, Y., Pattada, N., Zhong, W., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40850-5 · Cited by 272 · see citing works
Helms, E. J., Berry, M. W., Chaw, R. C., DuFort, C. C., Sun, D., Onate, M. K., Oon, C., Bhattacharyya, S., Sanford-Crane, H., Horton, W., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0601 · Cited by 238 · see citing works
The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis
Kobayashi, H., Gieniec, K. A., Lannagan, T. R. M., Wang, T., Asai, N., Mizutani, Y., Iida, T., Ando, R., Thomas, E. M., Sakai, A., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2021.11.037 · Cited by 214 · see citing works
“Interestingly, a recent paper found that Gli1þ pancreatic stellate cells could contribute to approximately half of ACTA2þ CAFs in a mouse model of pancreatic cancer.(33) Further research is required to determine the hierarchic or overlapping relationship between Lepr-lineage and Gli1-lineage CAFs in different tissues…”
BackgroundArginase 1 is a key driver of immune suppression in pancreatic cancer
Menjivar, R. E., Nwosu, Z. C., Du, W., Donahue, K. L., Hong, H. S., Espinoza, C. E., Brown, K. L., Velez-Delgado, A., Yan, W., Lima, F., et al. (2023) · eLife · doi:10.7554/elife.80721 · Cited by 180 · see citing works
“The dualrecombinase system integrates both FlippaseFRT (FlpFRT) and Cre- loxP recombination technologies to independently modify epithelial cells and myeloid cells (Garcia et al., 2020; Wen et al., 2019).”
BackgroundMethodInfluentialSelf-citationHarnessing metabolic dependencies in pancreatic cancers
Encarnación-Rosado, J., & Kimmelman, A. C. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00431-7 · Cited by 180 · see citing works
Hox genes in development and beyond
Hubert, K. A., & Wellik, D. M. (2023) · Development · doi:10.1242/dev.192476 · Cited by 120 · see citing works
Self-citationExtrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming
Velez-Delgado, A., Donahue, K. L., Brown, K. L., Du, W., Irizarry-Negron, V., Menjivar, R. E., Lasse Opsahl, E. L., Steele, N. G., The, S., Lazarus, J., et al. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.02.016 · Cited by 91 · see citing works
“cells), but recent lineage tracing work by our group has shown that a substantial proportion of CAFs derive from perivascular fibroblasts present in the normal pancreas.(68) Accordingly, a lineage tracing study following pancreatic stellate cells in pancreatic cancer showed that they only contribute to a small subset…”
BackgroundSelf-citationQin, Q., Yu, R., Eriksson, J., Tsai, H., & Zhu, H. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216859 · Cited by 101 · see citing works
Vaish, U., Jain, T., Are, A. C., & Dudeja, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413408 · Cited by 94 · see citing works
“further shed light on the heterogenous fibroblastic precursors of CAFs in PDAC when they performed lineage-tracing studies using Gli1 and Hoxb6, two mesenchymal markers that have not been associated with stellate cells [43].”
BackgroundLi, T., Hu, C., Huang, T., Zhou, Y., Tian, Q., Chen, H., He, R., Yuan, Y., Yong, J., Jiang, H., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-3173 · Cited by 94 · see citing works
“47), CD105 + and CD105 � CAFs, LRRC15 + CAFs (48), Gli1 + CAFs, and Hoxb6 + CAFs (49), among others, and each sub-type has a distinct influence on tumor dynamics (46).”
Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer
Mello, A. M., Ngodup, T., Lee, Y., Donahue, K. L., Li, J., Rao, A. U. K., Carpenter, E. S., Crawford, H. C., di Magliano, M. P., & Lee, K. E. (2022) · Oncogenesis · doi:10.1038/s41389-022-00434-2 · Cited by 91 · see citing works
“However, recent reports suggest that besides PSCs, PDAC CAFs can arise from multiple cell types [33, 34].”
BackgroundSelf-citationTranscription factors in fibroblast plasticity and CAF heterogeneity
Melchionna, R., Trono, P., Carlo, A. D., Modugno, F. D., & Nisticò, P. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02934-4 · Cited by 87 · see citing works
“…in liver fibrosis [25] Normal fibroblast conversion into CAFs GLI1 Specific Gli1 + fibroblasts expansion in tumor stroma during carcinogenesis [26] TBX4 Lost during lung CAF activation Promotes fibroblast proliferation and collagen gel contraction capacity [27] CSL/p53 complex Lost during…”
BackgroundCancer‐associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets
Menezes, S., Okail, M. H., Jalil, S. M. A., Kocher, H. M., & Cameron, A. J. M. (2022) · The Journal of Pathology · doi:10.1002/path.5926 · Cited by 79 · see citing works
“Garcia et al reported distinct Gli1 and HoxB6 fibroblast lineages in the healthy mouse pancreas, which can both contribute significantly to KF (Ptf1aFlpO/+;KrasFSF-G12D/+) and KPF (Ptf1aFlpO/+;KrasFSF-G12D/+; Trp53FRT-STOP-FRT/+)-driven tumour CAFs, with Gli1+ cells dominating [68].”
BackgroundMasugi, Y. (2022) · Cancers · doi:10.3390/cancers14133293 · Cited by 81 · see citing works
“A recent study using a lineage-tracing platform has revealed differential contributions between two differentially located resident fibroblasts (GLI family zinc finger 1 (GLI1)+ fibroblasts and homeobox B6 (HOXB6)+ fibroblasts) to CAF generation during murine PDAC carcinogenesis [99].”
BackgroundMacrophages and fibroblasts as regulators of the immune response in pancreatic cancer
Shakiba, M., & Tuveson, D. A. (2025) · Nature Immunology · doi:10.1038/s41590-025-02134-6 · Cited by 75 · see citing works
“However, PSCs were later shown to constitute only a minority of CAFs, whereas other cell types, such as pericytes, adipocytes, endothelial cells and mesothelial cells, were shown to also contribute to the generation of CAFs in PDAC 39–42 (Fig.”
Zheng, S., Hu, C., Lin, Q., Li, T., Li, G., Tian, Q., Zhang, X., Huang, T., Ye, Y., He, R., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0178 · Cited by 64 · see citing works
“CAF subpopulations like myCAFs, iCAFs, and others influence tumor dynamics ( 7 , 29 – 33 ).”
BackgroundHerting, C. J., Karpovsky, I., & Lesinski, G. B. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-09988-w · Cited by 61 · see citing works
Sunami, Y., Häußler, J., & Kleeff, J. H. (2020) · Cancers · doi:10.3390/cancers12123770 · Cited by 62 · see citing works
“In a pancreatic cancer mouse model (Ptf1-Cre; frp-stop-frp-KrasG12D/+; Gli1CreERT), lineage-traced, GLI1-positive cells account for a little less than half of the total myofibroblast population [45].”
BackgroundInfluentialDonahue, K. L., Watkoske, H. R., Kadiyala, P., Du, W., Brown, K. L., Scales, M. K., Elhossiny, A. M., Espinoza, C. E., Opsahl, E. L. L., Griffith, B. D., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0100 · Cited by 58 · see citing works
“Likewise, the mechanism through which normal fibroblasts and other cells of the healthy pancreas are converted to PAFs and CAFs also remains unclear.”
InfluentialSelf-citationThe fibroinflammatory response in cancer
Xiao, Z., & Puré, E. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00798-8 · Cited by 60 · see citing works
Yan, W., Menjivar, R. E., Bonilla, M. E., Steele, N. G., Kemp, S. B., Du, W., Donahue, K. L., Brown, K. L., Carpenter, E. S., Avritt, F. R., et al. (2023) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-23-0037 · Cited by 52 · see citing works
Self-citationA bird’s eye view of fibroblast heterogeneity: A pan‐disease, pan‐cancer perspective
Pradhan, R., Krishnamurty, A. T., Fletcher, A. L., Turley, S. J., & Müller, S. (2021) · Immunological Reviews · doi:10.1111/imr.12990 · Cited by 51 · see citing works
Pancreatic Fibroblast Heterogeneity: From Development to Cancer
Garcia, P. E., Scales, M. K., Allen, B. L., & di Magliano, M. P. (2020) · Cells · doi:10.3390/cells9112464 · Cited by 46 · see citing works
“Gli1 Lineage Derived from Gli1+ fibroblasts in healthy pancreas Not fully understood Partially contributes to myCAFs [28]”
BackgroundSelf-citationA Quick Guide to CAF Subtypes in Pancreatic Cancer
Brichkina, A. I., Polo, P., Sharma, S. D., Visestamkul, N., & Lauth, M. (2023) · Cancers · doi:10.3390/cancers15092614 · Cited by 40 · see citing works
“However, one recent study used lineage-tracing experiments to delineate the origins of Gli1+ mesenchymal cells in murine PDAC [84].”
BackgroundCancer-Associated Fibroblasts: Lessons from Pancreatic Cancer
Sherman, M. H., & di Magliano, M. P. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061421-035400 · Cited by 37 · see citing works
Ganguly, K., Cox, J. L., Ghersi, D., Grandgenett, P. M., Hollingsworth, M. A., Jain, M., Sushil Kumar, K., & Batra, S. K. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.02.032 · Cited by 39 · see citing works
Murphy, K. J., Chambers, C. R., Herrmann, D., Timpson, P., & Pereira, B. (2021) · Cancers · doi:10.3390/cancers13143481 · Cited by 38 · see citing works
“The progenitors of these CAF subpopulations are yet to be fully elucidated, however Garcia et al. (2020) recently reported that some myCAFs could be derived from GLI1+ fibroblast progenitors [47].”
BackgroundCancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic Cancer
Peiffer, R., Boumahd, Y., Gullo, C., Crake, R., Letellier, E., Bellahcène, A., & Peulen, O. (2022) · Cancers · doi:10.3390/cancers15010061 · Cited by 37 · see citing works
“In another study, healthy fibroblasts were discriminated, based on GLI1 and HOXB6 expression and upon lineage tracing; both populations only partially contributed to the PDAC CAF landscape [13].”
Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer
Scales, M. K., Velez-Delgado, A., Steele, N. G., Schrader, H. E., Stabnick, A. M., Yan, W., Mercado-Soto, N. M., Nwosu, Z., Johnson, C. N., Zhang, Y.-Q., et al. (2022) · PLoS Genetics · doi:10.1371/journal.pgen.1010315 · Cited by 28 · see citing works
“To target Gli2 and Gli3 in fibroblasts in vivo, we crossed the Pdgfrα allele [49] into Kras;Ptf1a (KF) [50] mice.”
BackgroundMethodSelf-citationTumor Microenvironment in Pancreatic Intraepithelial Neoplasia
Opitz, F. V., Häberle, L., Daum, A., & Esposito, I. (2021) · Cancers · doi:10.3390/cancers13246188 · Cited by 30 · see citing works
“This fibroblast population upregulated the expression of Gli1 and was found in the progression to PDAC over PanIN lesions [61].”
BackgroundPancreatic Cancer–Associated Fibroblasts: Where Do We Go from Here?
Carpenter, E. S., Costa, D. B. V., Hasselluhn, M. C., Maitra, A., Olive, K. P., Cukierman, E., di Magliano, M. P., & Sherman, M. H. (2024) · Cancer Research · doi:10.1158/0008-5472.can-24-2860 · Cited by 28 · see citing works
Stromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity
Jia, D., Zhou, Z., Kwon, O., Zhang, L., Wei, X., Zhang, Y., Yi, M., Roudier, M. P., Regier, M. C., Dumpit, R. F., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34665-z · Cited by 30 · see citing works
Self-citationMacena, Y. D. O., Cezar, M. E. N., Lira, C. B. F., Oliveira, L. B. D. M. D., Almeida, T. N., Costa, A., Araujo, B. M. D. D., Junior, D. D. A., Dantas, H. M., Mélo, E. C. D., et al. (2024) · Cancer and Metastasis Reviews · doi:10.1007/s10555-024-10233-3 · Cited by 26 · see citing works
Fibroblast Subsets in Intestinal Homeostasis, Carcinogenesis, Tumor Progression, and Metastasis
Dang, H., Harryvan, T. J., & Hawinkels, L. J. A. C. (2021) · Cancers · doi:10.3390/cancers13020183 · Cited by 26 · see citing works
Giustarini, G., Teng, G., Pavesi, A., & Adriani, G. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1156769 · Cited by 27 · see citing works
Pereira, B., Ritchie, S., Chambers, C. R., Gordon, K. A., Magenau, A., Murphy, K. J., Nobis, M., Tyma, V. M., Liew, Y. F., Lucas, M. C., et al. (2024) · Science Advances · doi:10.1126/sciadv.adl1197 · Cited by 25 · see citing works
“Although vascular CAFs have not been explicitly identified as a separate CAF subpopulation in pancreatic cancer, Garcia et al. ( 13 ) recently identified that perivascular Gli1 + - resident fibroblasts are one of the main origins of CAFs in murine pancreatic tumors using lineage-tracing models.”
The plasticity of cancer-associated fibroblasts
Xia, Z., & Wever, O. D. (2025) · Trends in cancer · doi:10.1016/j.trecan.2025.04.012 · Cited by 27 · see citing works
Barrera, L. N., Ridley, P., Bermejo‐Rodríguez, C., Costello, E., & Pérez-Mancera, P. A. (2022) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-022-00899-0 · Cited by 20 · see citing works
“Interestingly, Gli1+ fibroblasts express αSMA and may represent early precursors of the myCAF population [34].”
BackgroundCancer-Associated Fibroblast Heterogeneity in Malignancy with Focus on Oral Squamous Cell Carcinoma
Arebro, J., Lee, C.-M., Bennewith, K. L., & Garnis, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25021300 · Cited by 21 · see citing works
“CAFs may originate from normal tissue fibroblasts, as reported by others [20], with lineage tracing studies in genetically engineered mouse models supporting this concept [21].”
MethodResultSaúde-Conde, R., Öztürk, A. A., Stosic, K., Senar, O. A., Navez, J., Bouchart, C., Arsenijevic, T., Flamen, P., & Laethem, J. V. (2024) · Biomedicines · doi:10.3390/biomedicines12030591 · Cited by 20 · see citing works
Challenges and Opportunities in Targeting the Complex Pancreatic Tumor Microenvironment
Finan, J. M., Guo, Y., Goodyear, S. M., & Brody, J. R. (2024) · JCO oncology advances. · doi:10.1200/oa-24-00050 · Cited by 20 · see citing works
Salas-Escabillas, D. J., Hoffman, M. T., Brender, S. M., Moore, J. S., Wen, H., Benitz, S., Davis, E. T., Long, D., Wombwell, A. M., Chianis, E. R. D., et al. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.12.003 · Cited by 20 · see citing works
Self-citationMolecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts
Liu, Y., Chen, X., Dai, Y., Jia, Y., Kieffer, Y., Xie, L., Zhou, Z., Tyler, L. A., Kim, A. C., Biffi, G., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2026.06.001 · Cited by 19 · see citing works
An integrated study to decipher immunosuppressive cellular communication in the PDAC environment
Avşar, G., & Pir, P. (2023) · npj Systems Biology and Applications · doi:10.1038/s41540-023-00320-6 · Cited by 19 · see citing works
Lloyd, E. G., Jihad, M., Manansala, J. S., Li, W., Cheng, P. S. W., Teles, S. P., Mucciolo, G., Henríquez, J. A., Ashworth, S., Luo, W., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-2330 · Cited by 18 · see citing works
Fibroblast heterogeneity in pancreatic ductal adenocarcinoma: Perspectives in immunotherapy
Luong, T., Golivi, Y., Nagaraju, G. P., & El‐Rayes, B. F. (2022) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2022.09.001 · Cited by 18 · see citing works
Sun, L., Zheng, M., Gao, Y., Brigstock, D. R., & Gao, R. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176374 · Cited by 20 · see citing works
Organotypic Culture of Acinar Cells for the Study of Pancreatic Cancer Initiation
Carrer, A., & Paoli, C. (2020) · Cancers · doi:10.3390/cancers12092606 · Cited by 16 · see citing works
Targeting the Stromal Pro-Tumoral Hyaluronan-CD44 Pathway in Pancreatic Cancer
Koltai, T., Reshkin, S. J., Carvalho, T. M. A., & Cardone, R. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083953 · Cited by 15 · see citing works
“creas which expands during carcinogenesis with a different prevalence according to subtypes [22].”
BackgroundGraham, S., Dmitrieva, M., Costa, D. B. V., Francescone, R., Trujillo, M. A. M., Cukierman, E., & Wood, L. D. (2024) · Carcinogenesis · doi:10.1093/carcin/bgae064 · Cited by 15 · see citing works
Ando, R., Shiraki, Y., Miyai, Y., Shimizu, H., Furuhashi, K., Minatoguchi, S., Kato, K., Kato, A., Iida, T., Mizutani, Y., et al. (2023) · The Journal of Pathology · doi:10.1002/path.6211 · Cited by 13 · see citing works
Heterocellular crosstalk and architecture of the pancreatic tumour microenvironment
Arnold, F., Vecchio, A. D., Hussain, Z., & Sherman, M. H. (2026) · Nature reviews. Cancer · doi:10.1038/s41568-025-00905-9 · Cited by 14 · see citing works
Heterogeneity and plasticity of cancer-associated fibroblasts
Pramod, S., Lavon, H., Scherz‐Shouval, R., & Sherman, M. H. (2026) · Nature Cancer · doi:10.1038/s43018-026-01146-x · Cited by 14 · see citing works
Spatiotemporal signaling underlies progressive vascular rarefaction in myocardial infarction
Tung, L. W., Groppa, E., Soliman, H., Lin, B., Chang, C.-K., Cheung, C. W., Ritso, M., Guo, D., Rempel, L., Sinha, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-44227-6 · Cited by 12 · see citing works
Heterogeneity in Pancreatic Cancer Fibroblasts—TGFβ as a Master Regulator?
Watt, D. M., & Morton, J. P. (2021) · Cancers · doi:10.3390/cancers13194984 · Cited by 12 · see citing works
Reyes, J., Priore, I. S. D., Chaikovsky, A. C., Pasnuri, N., Elhossiny, A. M., Park, J., Weiler, P., Krause, T., Moorman, A. R., Snopkowski, C., et al. (2026) · Cell · doi:10.1016/j.cell.2026.03.032 · Cited by 11 · see citing works
Hox genes and patterning the vertebrate body
Wellik, D. M. (2024) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2024.02.011 · Cited by 11 · see citing works
Self-citationStromal fibrin shapes immune infiltration landscape of pancreatic ductal adenocarcinoma
Karim, M., Hasan, M. M., Kim, S. H., Azam, Z., Wahab, R., Islam, T., Alam, F., Kim, Y.-J., Bae, D., Roy, S., et al. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123280 · Cited by 11 · see citing works
Vera, R. E., Lamberti, M. J., Almada, L. L., Tolosa, E. J., Vrabel, A. M., Sigafoos, A. N., Toruner, M. D., Flores, L. F., Rivarola, V. A., Vittar, N. B. R., et al. (2023) · Biochemical Journal · doi:10.1042/bcj20220521 · Cited by 11 · see citing works
Kou, Z., Liu, C., Zhang, W., Sun, C., Liu, L., & Zhang, Q. (2024) · International Journal of Oncology · doi:10.3892/ijo.2024.5642 · Cited by 11 · see citing works
“Through lineage tracing, Garcia et al (76) found that resident Gli1+ fibroblasts, which are distinct from PSCs in healthy pancreas, may a source of myCAF populations, providing clues for this hypothesis.”
BackgroundCancer-associated fibroblasts mediate resistance to anti-EGFR therapies in cancer
Dai, S., Liu, Y., Liu, Z., Li, R., Luo, F., Li, Y., Dai, L., & Peng, X. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107304 · Cited by 10 · see citing works
Spatially organized cellular communities shape functional tissue architecture in the pancreas
Torres-Cano, A., Darrigrand, J.-F., Herrera-Oropeza, G. E., Goss, G., Willnow, D., Salowka, A., Ma, S., Chitnis, D., Rouault, M., Vigilante, A., et al. (2025) · Science Advances · doi:10.1126/sciadv.adx5791 · Cited by 10 · see citing works
“Notably, it has been shown that not all resident fibroblast populations expand upon injury and transition into cancer-associated fibroblasts within the pancreas ( 56 – 58 ).”
Cellular collusion: cracking the code of immunosuppression and chemo resistance in PDAC
Musiu, C., Lupo, F., Agostini, A., Lionetto, G., Bevere, M., Paiella, S., Carbone, C., Corbo, V., Ugel, S., & Sanctis, F. D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1341079 · Cited by 9 · see citing works
Cancer-associated fibroblasts in acute leukemia
Gu, L., Liao, P. H., & Liu, H. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1022979 · Cited by 8 · see citing works
McAndrews, K. M., Mahadevan, K. K., & Kalluri, R. (2024) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041411 · Cited by 8 · see citing works
Concerted BAG3 and SIRPα blockade impairs pancreatic tumor growth
Marco, M. D., Gauttier, V., Pengam, S., Mary, C., Ranieri, B., Basile, A. M., Festa, M., Falco, A., Reppucci, F., Cammarota, A. L., et al. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-00817-9 · Cited by 7 · see citing works
CAFomics: convergence to translation for precision stroma approaches
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Seidel, T., Ohri, N., Glaß, M., Sunami, Y., Müller, L. P., & Kleeff, J. H. (2025) · Cancers · doi:10.3390/cancers17091541 · Cited by 7 · see citing works
“Currently, no unique markers distinguish pancreatic fibroblasts from fibroblasts in other organs [20].”
Bahng, I. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1713123 · Cited by 6 · see citing works
Tracing the Origin of Fibroblasts in Pancreatic Cancer
Biffi, G. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.06.008 · Cited by 6 · see citing works
Type 2 diabetes alters quiescent pancreatic stellate cells to tumor-prone state
Hara, Y., Mizukami, H., Yamada, T., Shimoyama, S., Yamazaki, K., Sasaki, T., Wang, Z., Kushibiki, H., Ryuzaki, M., Ogasawara, S., et al. (2025) · JCI Insight · doi:10.1172/jci.insight.187424 · Cited by 6 · see citing works
“Pdpn , Pdgfra , S100a4 , Fap , Cd34 , and Acta2 are known as PSC markers (14, 25, 26).”
Khouzam, R. A., Salman, S., Thiery, J., Zaarour, R. F., Vela, V., Limani, P., Janji, B., & Chouaı̈b, S. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27093873 · Cited by 5 · see citing works
“In PDAC, resident quiescent pancreatic stellate cells (PSCs) are thought to be the primary source of CAFs [44].”
Zhang, G., Shu, Z., Yu, J. Q., Li, J., Yi, P., Wu, B., Deng, D., Yan, S., Li, Y., Ren, D., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1341209 · Cited by 5 · see citing works
Paracrine regulation of pancreatic cancer cell response to chemotherapy by GLI2–collagen I signaling
Vera, R. E., Fernadez-Barrena, M. G., Falero, J. M., Kwon, J., Garza, R. A., Sigafoos, A. N., Ross, M. D., Toruner, M. D., Toruner, M., Tolosa, E. J., et al. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110311 · Cited by 4 · see citing works
Lloyd, E. G., Henríquez, J. A., & Biffi, G. (2024) · Disease Models & Mechanisms · doi:10.1242/dmm.050624 · Cited by 4 · see citing works
“Malignant cell-dependent reprogramming and distinct cells of origin have been shown to contribute to CAF heterogeneity and function (Öhlund et al., 2017; Biffi et al., 2019; Biffi and Tuveson, 2020; Garcia et al., 2020; Helms et al., 2021; Hutton et al., 2021).”
Stromal KITL/SCF Maintains Pancreas Tissue Homeostasis and Restrains Tumor Progression
Oñate, M. K., Oon, C. H., Bhattacharyya, S., Low, V., Chen, C., Zhao, X., Arnold, F., Yan, Z., Pramod, S., Hang, Y., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1079 · Cited by 4 · see citing works
“To further understand Kitl expression patterns in the pancreatic mesenchyme, we used standard density centrifugation to isolate PSCs from the gradient interface (30) and also isolated PDGFR α + pancreatic fibroblasts from the lower layers of the gradient (31).”
Handschin, C., Shalhoub, H., Mazet, A., Guyon, C., Dusserre, N., Boutet-Robinet, E. A., Oliveira, H., & Guillermet‐Guibert, J. (2025) · Biofabrication · doi:10.1088/1758-5090/adb51c · Cited by 4 · see citing works
Periostin-positive stellate cells associated with perineural invasion in pancreatic adenocarcinoma
Fraga, C. A. D. C., Santos, C. R. E. S., Lima, K. F. B., Rodrigues, G., Porto, C. C. F. N., de Menezes, M. N., da Silva, G. V. L., Simizo, A., Duarte, A. K. D. S. F., Baggio, J. A. D. O., et al. (2025) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2025.112678 · Cited by 3 · see citing works
Netrin G1 Ligand is a new stromal immunomodulator that promotes pancreatic cancerPreprint
Costa, D. B. V., Francescone, R. A., III, Franco‐Barraza, J., Luong, T., Graves, M., de Aquino, A. M., Steele, N. G., Gardiner, J. C., dos Santos, S. A. A., Ogier, C., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.15.594354 · Cited by 3 · see citing works
Wilms Tumor 1–Expressing Stromal Cells Promote Pancreatic Cancer Progression
Bischoff, A. C., Brown, K. L., Lasse-Opsahl, E., Watkoske, H. R., Espinoza, C. E., Okoye, J., Olivei, A., Green, L. M., Rai, R., The, S., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-25-1014
“Human PDAC samples were acquired from patients referred for Whipple or distal pancreatectomy according to Institutional Review Board protocol HUM000025339.”
InfluentialSelf-citationCancer-Associated Fibroblasts: Heterogeneity and Bimodality in Oncogenesis
Lunina, N. A., Safina, D. R., & Kostrov, S. V. (2023) · Molecular Biology · doi:10.31857/s0026898423050105 · Cited by 2 · see citing works
Integrins in Cancer: Refocusing on the Tumor Microenvironment
Zeltz, C., Lü, N., Heljäsvaara, R., & Gullberg, D. (2022) · Biology of extracellular matrix · doi:10.1007/978-3-030-99708-3_11 · Cited by 2 · see citing works
Cancer-Associated Fibroblasts: Heterogeneity and Bimodality in Oncogenesis
Lunina, N. A., Safina, D. R., & Kostrov, S. V. (2023) · Molecular Biology · doi:10.1134/s0026893323050096 · Cited by 1 · see citing works
Bertonnier‐Brouty, L., Bsharat, S., Achanta, K., Andersson, J., Pranomphon, T., Singh, T., Kaprio, T., Hagström, J., Haglund, C. H., Seppänen, H. E., et al. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00292-5 · Cited by 1 · see citing works
“…of the microRNA miR-2682-5p in a signaling cascade involving LINC01006-miR-2682-5p-HOXB8 that promotes pancreatic cancer proliferation and metastasis [47], while HOXB6 expression has been reported previously in mouse pancreatic fibroblasts which were not associated with the tumor stroma [23].”
Singh, R., Yousefian, N., Allen, W. M., Silva, A. D., Anaraki, C., Michels, A. K., Calderon, S. E., Loveless, I. M., Rastelli, D., George, A., et al. (2026) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2026.101872 · Cited by 1 · see citing works
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Origin, activation and heterogeneity of fibroblasts associated with pancreas and breast cancers
Han, L., Seward, C., Leone, G. W., & Ostrowski, M. C. (2022) · Advances in cancer research · doi:10.1016/bs.acr.2022.03.003 · Cited by 1 · see citing works
HOXB6 and HOXB8 control immune-cancer cell interactions in pancreatic cancerPreprint
Bertonnier‐Brouty, L., Achanta, K., Andersson, J., Bsharat, S., Singh, T., Kaprio, T., Hagström, J., Haglund, C., Seppänen, H. E., Prasad, R. B., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.06.611619 · Cited by 1 · see citing works
Zhang, B., & Shang, D. (2026) · Molecular Cancer · doi:10.1186/s12943-026-02656-z · Cited by 1 · see citing works
“Accumulating evidence indicates that fibroblasts comprise heterogeneous subpopulations with distinct transcriptional programs and functional roles, some of which may not originate directly from PSCs [5, 6].”
Tracing back to one of the origins of immune evasion in pancreatic cancer
Henríquez, J. A., & Biffi, G. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.05.002
O’Fee, K., Burley, A., & Wilkins, A. C. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-14064-8.00005-9
O’Fee, K., Burley, A., & Wilkins, A. C. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-14064-8.90005-5
- Authors
- Garcia, P. E., Adoumie, M., Kim, E. C., Zhang, Y., Scales, M. K., El-Tawil, Y. S., Shaikh, A. Z., Wen, H.-J., Bednar, F., Allen, B. L., Wellik, D. M., Crawford, H. C., & Pasca di Magliano, M.
- Affiliations
- University of Michigan (US)
- University of Wisconsin–Madison (US)
- ORCID
- Venue
- Cellular and Molecular Gastroenterology and Hepatology
- Publisher
- Elsevier BV
- Published
- 2020
- Volume
- 10
- Issue
- 3
- Pages
- 581-599
- ISSN
- 2352-345X (ISSN-L)
- PMC
- PMC7399194
- OpenAlex
- W3027333363
- Cited by
- 110
- References
- 83
- Citations by year
- 2026: 16 · 2025: 16 · 2024: 25 · 2023: 18 · 2022: 16 · 2021: 14 · 2020: 5
- FWCI
- 4.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- pancreatic cancer, pancreatic stroma, pancreatic fibroblasts, fibroblast heterogeneity, Gli1, HOXB6, pancreatic intraepithelial neoplasia, carcinogenesis
- MeSH terms
- Zinc Finger Protein GLI1, Animals, Disease Models, Animal, Fibroblasts, Humans, Mice, Transgenic, Pancreas, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Homeodomain Proteins, Carcinoma, Pancreatic Ductal, Mice, Carcinogenesis
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