Cited by 239Pancreatic and Hepatic Oncology ResearchCancer Cells and MetastasisCellular Mechanics and Interactions

The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.

Mesenchymal lineage heterogeneity underlies nonredundant functions of pancreatic cancer-associated fibroblasts

Open access

Helms, Erin J., Berry, Mark W., Chaw, R. Crystal, DuFort, Christopher C., Sun, Duanchen, Onate, M. Kathrina, Oon, Chet, Bhattacharyya, Sohinee, Sanford-Crane, Hannah, Horton, Wesley, Finan, Jennifer M., Sattler, Ariana, Makar, Rosemary, Dawson, David W., Xia, Zheng, Hingorani, Sunil R., Sherman, Mara H.·2022·Cancer Discovery

DOI 10.1158/2159-8290.cd-21-0601PMC PMC8831457

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSC), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed nonredundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs and demonstrate unique functions for CAFs of a defined cellular origin. Significance: By tracking and ablating a specific CAF population, we find that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity and signaling gradients diversify PDAC CAFs. See related commentary by Cukierman, p. 296. This article is highlighted in the In This Issue feature, p. 275

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1158/2159-8290.cd-21-0601

Cites

59 of 59 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

A framework for advancing our understanding of cancer-associated fibroblasts
Sahai, E., Astsaturov, I., Cukierman, E., DeNardo, D. G., Egeblad, M., Evans, R. M., Fearon, D., Greten, F. R., Hingorani, S. R., Hunter, T., et al. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0238-1 · Cited by 3,863
Self-citation
A global double-fluorescent Cre reporter mouse
Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L., & Luo, L. (2007) · genesis · doi:10.1002/dvg.20335 · Cited by 3,491
Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer
Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M. A., Caldwell, M. E., Allard, D., et al. (2009) · Science · doi:10.1126/science.1171362 · Cited by 3,170
Self-citation
Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival
Özdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C.-C., Simpson, T. R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S. V., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.04.005 · Cited by 2,681
Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609
Self-citation
Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., Corbo, V., Oni, T. E., Hearn, S. A., Lee, E. J., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20162024 · Cited by 2,590
Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts
Elyada, E., Bolisetty, M., Laise, P., Flynn, W. F., Courtois, E. T., Burkhart, R. A., Teinor, J. A., Belleau, P., Biffi, G., Lucito, M. S., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0094 · Cited by 2,241
Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma
Provenzano, P. P., Cuevas, C., Chang, A. E., Goel, V. K., Von Hoff, D. D., & Hingorani, S. R. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.01.007 · Cited by 2,195
Self-citation
Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer
Feig, C., Jones, J. O., Kraman, M., Wells, R. J. B., Deonarine, A., Chan, D. S., Connell, C. M., Roberts, E. W., Zhao, Q., Caballero, O. L., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320318110 · Cited by 2,100
Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma
Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A., Dekleva, E. N., Saunders, T., Becerra, C. P., Tattersall, I. W., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.04.021 · Cited by 2,085

Flagged first, then by citations

Show all 59 references

Sorted by citations

The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth
de Visser, K. E., & Joyce, J. A. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.02.016 · Cited by 4,059
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
Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments
Yuan, Z., Li, Y., Zhang, S., Wang, X., Dou, H., Yu, X., Zhang, Z., Yang, S., & Xiao, M. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01744-8 · Cited by 977
The cancer-immunity cycle: Indication, genotype, and immunotype
Mellman, I., Chen, D. S., Powles, T. B., & Turley, S. J. (2023) · Immunity · doi:10.1016/j.immuni.2023.09.011 · Cited by 1,018
Cancer-associated fibroblasts in the single-cell era
Lavie, D., Ben‐Shmuel, A., Erez, N., & Scherz‐Shouval, R. (2022) · Nature Cancer · doi:10.1038/s43018-022-00411-z · Cited by 656
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
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 501
Self-citation
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 450
The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis
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
Conserved spatial subtypes and cellular neighborhoods of cancer-associated fibroblasts revealed by single-cell spatial multi-omics
Liu, Y., Sinjab, A. F., Min, J., Han, G., Paradiso, F., Zhang, Y., Wang, R., Pei, G., Dai, Y., Liu, Y., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.03.004 · Cited by 268
Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer
Niu, N., Shen, X., Wang, Z., Chen, Y., Weng, Y., Yu, F., Tang, Y., Lu, P., Liu, M., Wang, L., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.03.005 · Cited by 244
Nasopharyngeal carcinoma ecology theory: cancer as multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem
Luo, W. (2023) · Theranostics · doi:10.7150/thno.82690 · Cited by 242
Single-cell and spatial transcriptome analysis reveals the cellular heterogeneity of liver metastatic colorectal cancer
Wang, F., Long, J., Li, L., Wu, Z., Da, T.-T., Wang, X., Huang, C., Jiang, Y., Yao, X., Ma, H., et al. (2023) · Science Advances · doi:10.1126/sciadv.adf5464 · Cited by 263
Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin
Foster, D. S., Januszyk, M., Delitto, D., Yost, K. E., Griffin, M., Guo, J. L., Guardino, N. J., Delitto, A. E., Chinta, M. S., Burcham, A. R., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.09.015 · Cited by 220
Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma
Zhang, T., Ren, Y., Yang, P., Wang, J., & Zhou, H. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05351-1 · Cited by 240
EGFR-activated myofibroblasts promote metastasis of pancreatic cancer
Mucciolo, G., Henríquez, J. A., Jihad, M., Teles, S. P., Manansala, J. S., Li, W., Ashworth, S., Lloyd, E. G., Cheng, P. S. W., Luo, W., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.12.002 · Cited by 224
CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion
Günaydın, G. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.668349 · Cited by 211
Targeting CAFs to overcome anticancer therapeutic resistance
Saw, P. E., Chen, J., & Song, E. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.03.001 · Cited by 206
Combined MEK and STAT3 Inhibition Uncovers Stromal Plasticity by Enriching for Cancer-Associated Fibroblasts With Mesenchymal Stem Cell-Like Features to Overcome Immunotherapy Resistance in Pancreatic Cancer
Datta, J., Dai, X., Bianchi, A., Silva, I. D. C., Mehra, S., Garrido, V. T., Lamichhane, P., Singh, S. P., Zhou, Z., Dosch, A. R., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2022.07.076 · Cited by 183
Metabolic heterogeneity in cancer
Demicco, M., Liu, X., Leithner, K., & Fendt, S. (2024) · Nature Metabolism · doi:10.1038/s42255-023-00963-z · Cited by 186
Barriers and opportunities in pancreatic cancer immunotherapy
Ju, Y., Xu, D., Liao, M.-M., Sun, Y., Bao, W.-D., Yao, F., & Ma, L. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00681-z · Cited by 174
Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions
Carpenter, E. S., Elhossiny, A. M., Kadiyala, P., Li, J., McGue, J. J., Griffith, B. D., Zhang, Y., Edwards, J., Nelson, S., Lima, F., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0013 · Cited by 157
Schwann cells regulate tumor cells and cancer-associated fibroblasts in the pancreatic ductal adenocarcinoma microenvironment
Xue, M., Zhu, Y., Jiang, Y., Han, L., Shi, M., Su, R. J., Wang, L., Xiong, C., Wang, C., Wang, T., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40314-w · Cited by 153
Hypoxia Potentiates the Inflammatory Fibroblast Phenotype Promoted by Pancreatic Cancer Cell–Derived Cytokines
Schwörer, S., Cimino, F. V., Ros, M., Tsanov, K. M., Ng, C., Lowe, S. W., Carmona‐Fontaine, C., & Thompson, C. B. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-2316 · Cited by 147
Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context
Kerk, S. A., Lin, L., Myers, A. L., Sutton, D. J., Andren, A., Sajjakulnukit, P., Zhang, L., Zhang, Y., Jiménez, J. A., Nelson, B. S., et al. (2022) · eLife · doi:10.7554/elife.73245 · Cited by 108
From gatekeepers to providers: regulation of immune functions by cancer-associated fibroblasts
Arpinati, L., & Scherz‐Shouval, R. (2023) · Trends in cancer · doi:10.1016/j.trecan.2023.01.007 · Cited by 129
Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade
Lander, V. E., Belle, J. I., Kingston, N. L., Herndon, J. M., Hogg, G. D., Liu, X., Kang, L.-I., Knolhoff, B. L., Bogner, S. J., Baer, J. M., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0192 · Cited by 114
Epithelial and stromal co-evolution and complicity in pancreatic cancer
Hingorani, S. R. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00530-w · Cited by 108
Self-citation
Integration of Pan-Cancer Single-Cell and Spatial Transcriptomics Reveals Stromal Cell Features and Therapeutic Targets in Tumor Microenvironment
Du, Y., Shi, J., Wang, J., Xun, Z., Yu, Z., Sun, H., Bao, R., Zheng, J., Li, Z., & Ye, Y. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-1418 · Cited by 111
Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target
Hartupee, C. D., Nagalo, B. M., Chabu, C. Y., Tesfay, M. Z., Coleman‐Barnett, J., West, J. T., & Moaven, O. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1287459 · Cited by 116
Extrinsic 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
Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma therapy: Challenges and opportunities
Qin, Q., Yu, R., Eriksson, J., Tsai, H., & Zhu, H. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216859 · Cited by 102
Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting
Vaish, U., Jain, T., Are, A. C., & Dudeja, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413408 · Cited by 102
Autophagy loss impedes cancer-associated fibroblast activation via downregulating proline biosynthesis
Bai, J., Liu, T., Tu, B., Yuan, M., Shu, Z., Fan, M., Huo, S., Guo, Y., Wang, L., Wang, H., et al. (2022) · Autophagy · doi:10.1080/15548627.2022.2093026 · Cited by 95
BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling
Shaashua, L., Ben-Shmuel, A., Pevsner-Fischer, M., Friedman, G., Levi-Galibov, O., Nandakumar, S., Barki, D., Nevo, R., Brown, L. E., Zhang, W., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34081-3 · Cited by 79
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
The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth
Manoukian, P., Bijlsma, M. F., & van Laarhoven, H. W. M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.743907 · Cited by 95
Collagen architecture and signaling orchestrate cancer development
Su, H., & Karin, M. (2023) · Trends in cancer · doi:10.1016/j.trecan.2023.06.002 · Cited by 88
IL-17A-producing CD8 + T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts
Picard, F. S. R., Lutz, V., Brichkina, A. I., Neuhaus, F., Ruckenbrod, T., Hupfer, A., Raifer, H., Klein, M., Bopp, T., Pfefferle, P. I., et al. (2023) · Gut · doi:10.1136/gutjnl-2022-327855 · Cited by 88
Cancer‐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 82
The molecular classification of cancer‐associated fibroblasts on a pan‐cancer single‐cell transcriptional atlas
Chen, B., Chan, W. N., Xie, F., Mui, C. W., Liu, X., Cheung, A. H. K., Lung, R. W. M., Chow, C., Zhang, Z., Fang, C., et al. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1516 · Cited by 80
The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities
Masugi, Y. (2022) · Cancers · doi:10.3390/cancers14133293 · Cited by 90
Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer
Raymant, M., Astuti, Y., Álvaro‐Espinosa, L., Green, D. M., Quaranta, V., Bellomo, G., Glenn, M. A., Chandran-Gorner, V., Palmer, D. H., Halloran, C. M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47949-3 · Cited by 79
Integrative analysis of spatial and single-cell transcriptome data from human pancreatic cancer reveals an intermediate cancer cell population associated with poor prognosis
Kim, S., Leem, G., Choi, J., Koh, Y., Lee, S., Nam, S., Kim, J. S., Park, C. H., Hwang, H. K., Min, K. I., et al. (2024) · Genome Medicine · doi:10.1186/s13073-024-01287-7 · Cited by 81
Functional heterogeneity of fibroblasts in primary tumors and metastases
Cheng, P. S. W., Zaccaria, M., & Biffi, G. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.11.005 · Cited by 78
PanIN and CAF transitions in pancreatic carcinogenesis revealed with spatial data integration
Bell, A. T. F., Mitchell, J. T., Kiemen, A. L., Lyman, M. R., Fujikura, K., Lee, J. W., Coyne, E. M., Shin, S. M., Nagaraj, S., Deshpande, A. M., et al. (2024) · Cell Systems · doi:10.1016/j.cels.2024.07.001 · Cited by 77
Macrophages 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 81
The tumour microenvironment in pancreatic cancer — new clinical challenges, but more opportunities
Kung, H., Zheng, K., Zimmerman, J. W., & Zheng, L. (2025) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-025-01077-z · Cited by 86
Oncogenic KRAS-Dependent Stromal Interleukin-33 Directs the Pancreatic Microenvironment to Promote Tumor Growth
Donahue, 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 60
The fibroinflammatory response in cancer
Xiao, Z., & Puré, E. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00798-8 · Cited by 65
Dissecting FAP+ Cell Diversity in Pancreatic Cancer Uncovers an Interferon-Response Subtype of Cancer-Associated Fibroblasts with Tumor-Restraining Properties
Cumming, J., Maneshi, P., Dongre, M., Alsaed, T., Dehghan-Nayeri, M. J., Ling, A., Pietras, K., Patthey, C., & Öhlund, D. (2025) · Cancer Research · doi:10.1158/0008-5472.can-23-3252 · Cited by 61
Epigenetic regulation of cancer-associated fibroblast heterogeneity
Kehrberg, R. J., Bhyravbhatla, N., Batra, S. K., & Sushil Kumar, K. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188901 · Cited by 57
Notch Signaling Regulates Immunosuppressive Tumor-Associated Macrophage Function in Pancreatic Cancer
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
Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment
Han, X., Burrows, M., Kim, L. C., Xu, J. P., Vostrejs, W., Le, T. N. V., Poltorack, C. D., Jiang, Y., Cukierman, E., Stanger, B. Z., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114972 · Cited by 56
Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies
Linehan, A., O’Reilly, M., McDermott, R., & O'Kane, G. M. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1369136 · Cited by 57
Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer
Zhang, Y., Li, L., Murad, R., Maganti, S., Manceau, A., Faso, H. A., Neff, M., Galapate, C. M., Grenier, S. F., Carrette, F., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.06.021 · Cited by 57
HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation
Chia, L., Wang, B., Kim, J., Luo, L., Shuai, S., Herrera, I., Chen, S. Y., Li, L., Xian, L., Huso, T. H., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci151601 · Cited by 52
An integrated overview of the immunosuppression features in the tumor microenvironment of pancreatic cancer
Guo, J., Wang, S., & Gao, Q. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1258538 · Cited by 47
Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer
Veghini, L., Pasini, D., Fang, R., Delfino, P., Filippini, D., Neander, C., Vicentini, C., Fiorini, E., Lupo, F., D’Agosto, S. L., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54975-8 · Cited by 46
A 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 45
Targeting Cancer‐Associated Fibroblasts: Eliminate or Reprogram?
Yamazaki, M., & Ishimoto, T. (2025) · Cancer Science · doi:10.1111/cas.16443 · Cited by 40
Cancer-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 39
Self-citation
Mucin 5AC–Mediated CD44/ITGB1 Clustering Mobilizes Adipose-Derived Mesenchymal Stem Cells to Modulate Pancreatic Cancer Stromal Heterogeneity
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
Cancer-associated fibroblasts in the tumor microenvironment: heterogeneity, crosstalk mechanisms, and therapeutic implications
Huang, Z., Chen, J., Zhu, T., Li, J., Ng, H. Y., Zhou, Y., Gu, X., Xu, S., & Jia, R. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02533-1 · Cited by 49
Dynamic Stromal Alterations Influence Tumor-Stroma Crosstalk to Promote Pancreatic Cancer and Treatment Resistance
Murphy, K. J., Chambers, C. R., Herrmann, D., Timpson, P., & Pereira, B. (2021) · Cancers · doi:10.3390/cancers13143481 · Cited by 37
Therapeutic Strategies to Overcome Fibrotic Barriers to Nanomedicine in the Pancreatic Tumor Microenvironment
Tanaka, H. Y., Nakazawa, T., Enomoto, A., Masamune, A., & Kano, M. R. (2023) · Cancers · doi:10.3390/cancers15030724 · Cited by 42
Cancer-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 38
Roles of differently polarized macrophages in the initiation and progressionof pancreatic cancer
Störz, P. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1237711 · Cited by 36
Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma
Skorupan, N., Domínguez, M. P., Ricci, S. L., & Alewine, C. (2022) · Cancers · doi:10.3390/cancers14174209 · Cited by 35
High Throughput Confined Migration Microfluidic Device for Drug Screening
Yang, Z., Zhou, Z., Si, T., Zhou, Z., Zhou, L., Chin, Y. R., Zhang, L. N., Guan, X., & Yang, M. (2023) · Small · doi:10.1002/smll.202207194 · Cited by 33
Pancreatic cancer and fibrosis: Targeting metabolic reprogramming and crosstalk of cancer-associated fibroblasts in the tumor microenvironment
Li, X., Zhou, J., Wang, X., Li, C., Ma, Z., Wan, Q., & Fu, P. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1152312 · Cited by 38
A nanodrug simultaneously inhibits pancreatic stellate cell activation and regulatory T cell infiltration to promote the immunotherapy of pancreatic cancer
Wang, R., Hong, K., Zhang, Q., Cao, J., Huang, T., Xiao, Z., Wang, Y., & Shuai, X. (2023) · Acta Biomaterialia · doi:10.1016/j.actbio.2023.08.007 · Cited by 32
Sympathetic nerve signaling rewires the tumor microenvironment: a shift in “microenvironmental-ity”
Sattler, A. L., Korzun, T., Gupta, K. R., Diba, P., Kyprianou, N., & Eksi, S. E. (2025) · Cancer and Metastasis Reviews · doi:10.1007/s10555-025-10241-x · Cited by 36
Self-citation
Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia
Opitz, F. V., Häberle, L., Daum, A., & Esposito, I. (2021) · Cancers · doi:10.3390/cancers13246188 · Cited by 35
Pancreatic 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
Self-citation
Emerging role of pancreatic stellate cell-derived extracellular vesicles in pancreatic cancer
Sarkar, R., Xu, Z., Perera, C. J., & Apte, M. V. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.05.007 · Cited by 28
SERPINE1: Role in Cholangiocarcinoma Progression and a Therapeutic Target in the Desmoplastic Microenvironment
Czekay, R., Higgins, C. E., Aydin, H. B., Samarakoon, R., Subasi, N. B., Higgins, S. P., Lee, H., & Higgins, P. J. (2024) · Cells · doi:10.3390/cells13100796 · Cited by 27
Progress of single-cell RNA sequencing combined with spatial transcriptomics in tumour microenvironment and treatment of pancreatic cancer
Zhu, J., Zhang, K., Chen, Y., Ge, X., Wu, J., Xu, P., & Yao, J. J. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05307-3 · Cited by 30
Extracellular vesicles miR‐31‐5p promotes pancreatic cancer chemoresistance via regulating LATS2‐Hippo pathway and promoting SPARC secretion from pancreatic stellate cells
Qin, C. Y., Zhao, B., Wang, Y., Li, Z., Li, T., Zhao, Y., Wang, W., & Zhao, Y. (2024) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12488 · Cited by 29
Characterization of 3D heterocellular spheroids of pancreatic ductal adenocarcinoma for the study of cell interactions in the tumor immune microenvironment
Giustarini, G., Teng, G., Pavesi, A., & Adriani, G. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1156769 · Cited by 29
Insights into the relevance of targeting fibroblasts to control cancer
Boeker, V., & Kalluri, R. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102395 · Cited by 25
Next generation patient derived tumor organoids
Podaza, E., Kuo, H., Nguyen, J., Elemento, O., & Martín, M. L. (2022) · Translational research · doi:10.1016/j.trsl.2022.08.003 · Cited by 26
Statins abrogate gemcitabine-induced PD-L1 expression in pancreatic cancer-associated fibroblasts and cancer cells with improved therapeutic outcome
Minz, A. P., Mohapatra, D., Dutta, M., Sethi, M., Parida, D., Mohapatra, A. P., Mishra, S., Kar, S., Sasmal, P. K., & Senapati, S. (2023) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-023-03562-9 · Cited by 24
Periostin+ Stromal Cells Guide Lymphovascular Invasion by Cancer Cells
Null, J. L., Kim, D. J., McCann, J. V., Pramoonjago, P., Fox, J. W., Zeng, J., Kumar, P., Edatt, L., Pecot, C. V., & Dudley, A. C. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-2412 · Cited by 25
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
Self-citation
Purinergic signalling in cancer therapeutic resistance: From mechanisms to targeting strategies
Jia, W., Huang, Z., Zhou, L., Liou, Y., Virgilio, F. D., Ulrich, H., Illés, P., Zhang, W., Huang, C., & Tang, Y. (2023) · Drug Resistance Updates · doi:10.1016/j.drup.2023.100988 · Cited by 24
HGF/c-Met pathway inhibition combined with chemotherapy increases cytotoxic T-cell infiltration and inhibits pancreatic tumour growth and metastasis
Mekapogu, A. R., Xu, Z., Pothula, S. P., Perera, C. J., Pang, T., Hosen, S. M. Z., Damalanka, V. C., Janetka, J. W., Goldstein, D., Pirola, R. C., et al. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216286 · Cited by 21
Cancer-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 25
ANO6-mediated trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer cell growth and immune suppression
Ogier, C., Mercy, C. S. A., Bondarenko, E., Wu, Z., Lu, Z., Bui, Q. T., Dhamdhere, M. R., Tang, Y., Recoules, L., Klochkova, A., et al. (2026) · Nature Cancer · doi:10.1101/2023.09.15.557802 · Cited by 25
Rethinking the Roles of Cancer-Associated Fibroblasts in Pancreatic Cancer
Francescone, R., Crawford, H. C., & Costa, D. B. V. (2024) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2024.01.022 · Cited by 20
Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy
Murphy, K. J., Zhu, J., Trpceski, M., Pereira, B., Timpson, P., & Herrmann, D. (2022) · Biochemical Society Transactions · doi:10.1042/bst20220162 · Cited by 19
Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma or a Metaphor for Heterogeneity: From Single-Cell Analysis to Whole-Body Imaging
Saúde-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
CAFs-Associated Genes (CAFGs) in Pancreatic Ductal Adenocarcinoma (PDAC) and Novel Therapeutic Strategy
Yamashita, K., & Kumamoto, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25116003 · Cited by 20
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 21
Self-citation
Molecular 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
Self-citation
SMAD4 and KRAS Status Shapes Cancer Cell–Stromal Cross-Talk and Therapeutic Response in Pancreatic Cancer
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
Ym1+ macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer
Martinez, A. K. F., Döppler, H. R., Bastea, L. I., Edenfield, B. H., Liou, G., & Störz, P. (2022) · iScience · doi:10.1016/j.isci.2022.104327 · Cited by 18
Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer
Bryce, A. S., Dreyer, S. B., Froeling, F. E. M., & Chang, D. K.-F. (2022) · Cancers · doi:10.3390/cancers14215302 · Cited by 19
Hepatic signal transducer and activator of transcription‐3 signalling drives early‐stage pancreatic cancer cachexia via suppressed ketogenesis
Arneson‐Wissink, P. C., Mendez, H., Pelz, K. R., Dickie, J., Bartlett, A. Q., Worley, B. L., Krasnow, S. M., Eil, R. L., & Grossberg, A. J. (2024) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13466 · Cited by 18
PLXDC1 + Tumor‐Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma
Du, Y., Zhao, Y., Li, J., Wang, J., You, S., Zhang, Y., Zhang, L., Yang, J., Alinejad‐Rokny, H., Cheng, S., et al. (2025) · Advanced Science · doi:10.1002/advs.202415756 · Cited by 18

Authors: 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., Finan, J. M., Sattler, A., Makar, R., Dawson, D. W., Xia, Z., Hingorani, S. R., & Sherman, M. H.
Affiliations: Oregon Health & Science University (US)
Fred Hutch Cancer Center (US)
1Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon.
University of California, Los Angeles (US)
University of Washington (US)
Corresponding author: Sherman, Mara H.
ORCID: Chaw, R. Crystal
DuFort, Christopher C.
Onate, M. Kathrina
Oon, Chet
Sanford-Crane, Hannah
Finan, Jennifer M.
Sattler, Ariana
Dawson, David W.
Xia, Zheng
Hingorani, Sunil R.
Sherman, Mara H.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2021-09-21
Volume: 12
Issue: 2
Pages: 484-501
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-21-0601
PMC: PMC8831457
OpenAlex: W3199988150
Cited by: 238
References: 59
Citations by year: 2026: 41 · 2025: 49 · 2024: 52 · 2023: 54 · 2022: 34 · 2021: 8
FWCI: 13.57
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 143 d)
Locations: Cancer Discovery (publishedVersion, cc-by-nc-nd)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: National Institute of General Medical Sciences (T32 GM071338)
National Cancer Institute (R01 CA161112, U01 CA224193, R01 CA250917)
U.S. Department of Defense (W81XWH-18-1-0437)
Pew Charitable Trusts
Topics: Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords: cancer-associated fibroblasts, pancreatic ductal adenocarcinoma, pancreatic stellate cells, CAF heterogeneity, mesenchymal lineage, tumor microenvironment, extracellular matrix, tissue stiffness, cell of origin
MeSH terms: Cancer-Associated Fibroblasts, Animals, Female, Humans, Male, Pancreatic Neoplasms, Gene Expression Regulation, Neoplastic, Mice, Mesenchymal Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Mesenchymal lineage heterogeneity underlies nonredundant functions of pancreatic cancer-associated fibroblasts

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks