A Stromal Lysolipid–Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression
Open accessPublished version of a preprint
Abstract
Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features transdifferentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin–LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. Significance: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration. See related commentary by Biffi and Tuveson, p. 578. This article is highlighted in the In This Issue feature, p. 565
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
Cites
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?
Autophagy in stromal fibroblasts can generate alanine, which is subsequently used by PDAC cells to fuel the TCA cycle.
“Autophagy in stromal fibroblasts can generate alanine, which is subsequently used by pancreatic ductal adenocarcinoma (PDAC) cells to fuel the tricarboxylic acid (TCA) cycle126,130,131.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [131]
The Results (page not provided) state that autophagy-dependent alanine secretion by pancreatic stellate cells supports PDAC-cell mitochondrial metabolism. The paper does not specify that the alanine fuels the TCA cycle, so that more specific part of the claim is not supported by our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDifferential expression of solute carrier proteins can promote a one-way fibroblast-SLC1A4/PDAC-SLC38A2 exchange axis that enables alanine exchange.
“Differential expression of solute carrier proteins (SLCs) can also function to promote a one-way fibroblast-SLC1A4 / PDAC-SLC38A2 exchange axis, enabling the exchange of alanine253.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [253]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M., & Matrisian, L. M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0155 · Cited by 7,094 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells
Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J. A., Thompson, C. B., et al. (2013) · Nature · doi:10.1038/nature12138 · Cited by 1,683 · see citing works
Self-citationSherman, M. H., Yu, R. T., Engle, D. D., Ding, N., Atkins, A. R., Tiriac, H., Collisson, E. A., Connor, F., Van Dyke, T., Kozlov, S., et al. (2014) · Cell · doi:10.1016/j.cell.2014.08.007 · Cited by 1,158 · see citing works
Self-citationPancreatic stellate cells support tumour metabolism through autophagic alanine secretion
Sousa, C. M., Biancur, D. E., Wang, X., Halbrook, C. J., Sherman, M. H., Zhang, L., Kremer, D., Hwang, R. F., Witkiewicz, A. K., Ying, H., et al. (2016) · Nature · doi:10.1038/nature19084 · Cited by 1,122 · see citing works
Self-citationHyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer
Jacobetz, M. A., Chan, D. S., Neesse, A., Bapiro, T. E., Cook, N., Frese, K. K., Feig, C., Nakagawa, T., Caldwell, M. E., Zecchini, H. I., et al. (2013) · Gut · doi:10.1136/gutjnl-2012-302529 · Cited by 1,120 · see citing works
The emerging role of lysophosphatidic acid in cancer
Mills, G. B., & Moolenaar, W. H. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1143 · Cited by 1,097 · see citing works
Cancer-Associated Stromal Fibroblasts Promote Pancreatic Tumor Progression
Hwang, R. F., Moore, T. T., Arumugam, T., Ramachandran, V., Amos, K. D., Rivera, A. M., Ji, B., Evans, D. B., & Logsdon, C. D. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5714 · Cited by 1,093 · see citing works
Self-citationRambold, A. S., Cohen, S., & Lippincott-Schwartz, J. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.01.029 · Cited by 1,038 · see citing works
Identification, culture, and characterization of pancreatic stellate cells in rats and humans
Bachem, M. G., Schneider, E., Groß, H., Weidenbach, H., Schmid, R. M., Menke, A., Siech, M., Beger, H. G., Grünert, A., & Adler, G. (1998) · Gastroenterology · doi:10.1016/s0016-5085(98)70209-4 · Cited by 1,017 · see citing works
Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
Zhao, H., Yang, L., Baddour, J., Achreja, A., Bernard, V., Moss, T., Marini, J. C., Tudawe, T., Seviour, E. G., San Lucas, F. A., et al. (2016) · eLife · doi:10.7554/elife.10250 · Cited by 927 · see citing works
Kamphorst, J. J., Nofal, M., Commisso, C., Hackett, S. R., Lu, W., Grabocka, E., Vander Heiden, M. G., Miller, G., Drebin, J. A., Bar-Sagi, D., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2211 · Cited by 893 · see citing works
Self-citationLPA Receptors: Subtypes and Biological Actions
Choi, J. W., Herr, D. R., Noguchi, K., Yung, Y. C., Lee, C., Mutoh, T., Lin, M., Teo, S. T., Park, K. E., Austin, A. M., et al. (2010) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.010909.105753 · Cited by 840 · see citing works
Kamphorst, J. J., Cross, J. R., Fan, J., de Stanchina, E., Mathew, R., White, E. P., Thompson, C. B., & Rabinowitz, J. D. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1307237110 · Cited by 726 · see citing works
Self-citationStromal biology and therapy in pancreatic cancer: a changing paradigm
Neeße, A., Algül, H., Tuveson, D. A., & Gress, T. M. (2015) · Gut · doi:10.1136/gutjnl-2015-309304 · Cited by 562 · see citing works
Stromal response to Hedgehog signaling restrains pancreatic cancer progression
Lee, J. J., Perera, R. M., Wang, H., Wu, D.-C., Liu, X. S., Han, S., Fitamant, J., Jones, P. D., Ghanta, K. S., Kawano, S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411679111 · Cited by 502 · see citing works
Winograd, R., Byrne, K. T., Evans, R. A., Odorizzi, P. M., Meyer, A. R. L., Bajor, D. L., Clendenin, C., Stanger, B. Z., Furth, E. E., Wherry, E. J., et al. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0215 · Cited by 459 · see citing works
Self-citationA Starring Role for Stellate Cells in the Pancreatic Cancer Microenvironment
Apte, M. V., Wilson, J. S., Lugea, A., & Pandol, S. J. (2013) · Gastroenterology · doi:10.1053/j.gastro.2012.11.037 · Cited by 449 · see citing works
Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation
Tape, C. J., Ling, S., Dimitriadi, M., McMahon, K. M., Worboys, J. D., Leong, H. S., Norrie, I. C., Miller, C. J., Poulogiannis, G., Lauffenburger, D. A., et al. (2016) · Cell · doi:10.1016/j.cell.2016.03.029 · Cited by 369 · see citing works
Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins
Zhang, M., Martino, J. S. D., Bowman, R. L., Campbell, N. R., Baksh, S. C., Simon-Vermot, T., Kim, I. S., Haldeman, P. B., Mondal, C., Yong-Gonzales, V., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1371 · Cited by 368 · see citing works
Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors
Davidson, S. M., Jonas, O., Keibler, M. A., Hou, H. W., Luengo, A., Mayers, J. R., Wyckoff, J., Del Rosario, A. M., Whitman, M., Chin, C. R., et al. (2017) · Nature Medicine · doi:10.1038/nm.4256 · Cited by 331 · see citing works
A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
Collisson, E. A., Trejo, C. L., Silva, J. M., Gu, S., Korkola, J. E., Heiser, L. M., Charles, R., Rabinovich, B. A., Hann, B. C., Dankort, D. L., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0347 · Cited by 320 · see citing works
Beatty, G. L., Winograd, R., Evans, R. A., Long, K. B., Luque, S. L., Lee, J. W., Clendenin, C. J., Gladney, W. L., Knoblock, D. M., Guirnalda, P. D., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.010 · Cited by 293 · see citing works
Self-citationRegulation and Functions of Autophagic Lipolysis
Cingolani, F., & Czaja, M. J. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.06.003 · Cited by 140 · see citing works
Stellate Cells in Tissue Repair, Inflammation, and Cancer
Sherman, M. H. (2018) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100617-062855 · Cited by 102 · see citing works
Self-citationSaga, H., Ohhata, A., Hayashi, A., Katoh, M., Maeda, T., Mizuno, H., Takada, Y., Komichi, Y., Ota, H., Matsumura, N., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093230 · Cited by 57 · see citing works
Challenges in accurate quantitation of lysophosphatidic acids in human biofluids
Onorato, J. M., Shipkova, P. A., Minnich, A., Aubry, A., Easter, J. A., & Tymiak, A. A. (2014) · Journal of Lipid Research · doi:10.1194/jlr.d050070 · Cited by 41 · see citing works
Ridinger-Saison, M., DelGiorno, K. E., Zhang, T., Kraus, A., French, R. P., Jaquish, D., Tsui, C., Erikson, G. A., Spike, B. T., Shokhirev, M. N., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0189051 · Cited by 39 · see citing works
Self-citation
Flagged first, then by citations
Cited by
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 · see citing works
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 · see citing works
Self-citationReprogramming of fatty acid metabolism in cancer
Koundouros, N., & Poulogiannis, G. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0650-z · Cited by 1,621 · see citing works
Diversity and biology of cancer-associated fibroblasts
Biffi, G., & Tuveson, D. A. (2021) · Physiological Reviews · doi:10.1152/physrev.00048.2019 · Cited by 1,265 · see citing works
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
Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer
Snaebjornsson, M. T., Janaki-Raman, S., & Schulze, A. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.010 · Cited by 1,097 · see citing works
Bian, X., Liu, R. R., Meng, Y., Xing, D., Xu, D., & Lu, Z. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20201606 · Cited by 1,007 · see citing works
Lipid metabolism in cancer: New perspectives and emerging mechanisms
Broadfield, L. A., Pane, A. A., Talebi, A., Swinnen, J. V., & Fendt, S. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.04.013 · Cited by 763 · see citing works
Metabolites and the Tumour Microenvironment: From Cellular Mechanisms to Systemic Metabolism
Elia, I., & Haigis, M. C. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00317-z · Cited by 651 · see citing works
Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention
Butler, L. M., Perone, Y., Dehairs, J., Lupien, L. E., de Laat, V., Talebi, A., Loda, M. F., Kinlaw, W. B., & Swinnen, J. V. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.07.013 · Cited by 617 · see citing works
The role of lipids in cancer progression and metastasis
Martín‐Pérez, M., Urdiroz-Urricelqui, U., Bigas, C., & Benitah, S. A. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.09.023 · Cited by 577 · see citing works
High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites
Yang, J., Wei, H., Zhou, Y., Szeto, C. H., Li, C., Lin, Y., Coker, O. O., Lau, H. C.-H., Chan, A. W. H., Sung, J. J. �., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2021.08.041 · Cited by 540 · see citing works
Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics
Jin, H.-R., Wang, J., Wang, Z., Xi, M., Xia, B., Deng, K., & Yang, J. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01498-2 · Cited by 509 · 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
Self-citationLipids in the tumor microenvironment: From cancer progression to treatment
Corn, K. C., Windham, M. A., & Rafat, M. (2020) · Progress in Lipid Research · doi:10.1016/j.plipres.2020.101055 · Cited by 472 · see citing works
Stromal cells in the tumor microenvironment: accomplices of tumor progression?
Zhao, Y. F., Shen, M., Wu, L., Yang, H., Yao, Y., Yang, Q., Du, J., Liu, L., Li, Y., & Bai, Y. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06110-6 · Cited by 443 · see citing works
Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming
Li, Z., Sun, C., & Qin, Z. (2021) · Theranostics · doi:10.7150/thno.62378 · Cited by 396 · see citing works
Wang, S., Zheng, Y., Yang, F., Zhu, L., Zhu, X.-Q., Wang, Z.-F., Wu, X.-L., Zhou, C.-H., Yan, J.-Y., Hu, B.-Y., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00659-4 · Cited by 369 · see citing works
Metabolic Codependencies in the Tumor Microenvironment
Dey, P., Kimmelman, A. C., & DePinho, R. A. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1211 · Cited by 342 · see citing works
Microenvironmental Determinants of Pancreatic Cancer
Heßmann, E., Buchholz, S., Demir, İ. E., Singh, S. K., Gress, T. M., Ellenrieder, V., & Neeße, A. (2020) · Physiological Reviews · doi:10.1152/physrev.00042.2019 · Cited by 328 · see citing works
Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy
Fendt, S., Frezza, C., & Erez, A. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0844 · Cited by 320 · see citing works
Neurons release serine to support mRNA translation in pancreatic cancer
Banh, R. S., Biancur, D. E., Yamamoto, K., Sohn, A. S. W., Walters, B., Kuljanin, M., Gikandi, A., Wang, H., Mancias, J. D., Schneider, R. J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.016 · Cited by 292 · see citing works
Gong, J., Lin, Y., Zhang, H., Liu, C., Cheng, Z., Yang, X., Zhang, J., Xiao, Y., Jie, H., Qian, X., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2434-z · Cited by 287 · see citing works
Fibroblast Heterogeneity in the Pancreatic Tumor Microenvironment
Helms, E. J., Oñate, M. K., & Sherman, M. H. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1353 · Cited by 283 · see citing works
Self-citationHelms, 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
Self-citationNiu, 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 238 · see citing works
Cancer Cells Don’t Live Alone: Metabolic Communication within Tumor Microenvironments
Li, F., & Simon, M. C. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.06.018 · Cited by 226 · see citing works
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 215 · see citing works
Zhu, Z., Achreja, A., Meurs, N., Animasahun, O., Owen, S., Mittal, A., Parikh, P., Lo, T.-W., Franco-Barraza, J., Shi, J., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0226-5 · Cited by 204 · see citing works
Self-citationVasseur, S., & Guillaumond, F. (2022) · Oncogenesis · doi:10.1038/s41389-022-00420-8 · Cited by 198 · see citing works
Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer
Parker, S. J., Amendola, C. R., Hollinshead, K. E. R., Yu, Q., Yamamoto, K., Encarnación-Rosado, J., Rose, R. E., LaRue, M. M., Sohn, A. S. W., Biancur, D. E., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0959 · Cited by 175 · see citing works
Harnessing 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
KRAS Controls Pancreatic Cancer Cell Lipid Metabolism and Invasive Potential through the Lipase HSL
Rozeveld, C. N., Johnson, K. M., Zhang, L., & Razidlo, G. L. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-1255 · Cited by 162 · see citing works
Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment
García, C. J. G., Huang, Y., Fuentes, N. R., Turner, M. C., Monberg, M. E., Lin, D., Nguyen, N. D., Fujimoto, T. N., Zhao, J., Lee, J. J., et al. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.02.024 · Cited by 159 · see citing works
Zhang, F., Ma, Y., Li, D., Wei, J., Chen, K., Zhang, E., Liu, G., Chu, X., Liu, X., Liu, W., et al. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01600-2 · Cited by 158 · see citing works
Carcinogenesis of Pancreatic Ductal Adenocarcinoma
Störz, P., & Crawford, H. C. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.02.059 · Cited by 154 · see citing works
Lai, B. F. L., Lu, R. X. Z., Hu, Y., Davenport Huyer, L., Dou, W., Wang, E. Y., Radulovich, N., Tsao, M. S., Sun, Y., & Radisic, M. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202000545 · Cited by 142 · see citing works
Jena, B. C., Sarkar, S., Rout, L., & Mandal, M. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.08.002 · Cited by 137 · see citing works
Lipid Metabolism at the Nexus of Diet and Tumor Microenvironment
Peck, B., & Schulze, A. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.09.007 · Cited by 135 · see citing works
Cancer-associated fibroblasts: The chief architect in the tumor microenvironment
Sarkar, M., Nguyen, T., Gundre, E., Ogunlusi, O., El-Sobky, M. H., Giri, B., & Sarkar, T. R. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1089068 · Cited by 135 · see citing works
Borza, R., Salgado-Polo, F., Moolenaar, W. H., & Anastassis Perrakis, A. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101526 · Cited by 131 · see citing works
Miller, K. D., O’Connor, S., Pniewski, K. A., Kannan, T., Acosta, R., Mirji, G., Papp, S. B., Hulse, M., Mukha, D., Hlavaty, S. I., et al. (2023) · Nature Cancer · doi:10.1038/s43018-023-00636-6 · Cited by 132 · see citing works
Recent insights into the biology of pancreatic cancer
Yao, W., Maitra, A., & Ying, H. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102655 · Cited by 125 · see citing works
Zhang, Y., Recouvreux, M. V., Jung, M., Galenkamp, K. M. O., Li, Y., Zagnitko, O., Scott, D. A., Lowy, A. M., & Commisso, C. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0119 · Cited by 116 · see citing works
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 · see citing works
Newman, A. C., Falcone, M., Uribe, A. H., Zhang, T., Athineos, D., Pietzke, M., Vázquez, A., Blyth, K., & Maddocks, O. D. K. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.03.019 · Cited by 111 · see citing works
Metabolic interplays between the tumour and the host shape the tumour macroenvironment
Altea‐Manzano, P., Decker-Farrell, A. R., Janowitz, T., & Erez, A. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-024-00786-4 · Cited by 127 · see citing works
Crosstalk between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma
Sperb, N., Tsesmelis, M., & Wirth, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155486 · Cited by 103 · see citing works
Truong, L.-H., & Pauklin, S. (2021) · Cancers · doi:10.3390/cancers13195028 · Cited by 102 · see citing works
Ruze, R., Song, J., Yin, X., Chen, Y., Xu, R., Wang, C., & Zhao, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01376-w · Cited by 103 · 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
Li, 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
Zheng, S., Zou, Y., Tang, Y., Yang, A., Liang, J.-Y., Wu, L., Tian, W., Xiao, W., Xie, X., Yang, L., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2021.2020984 · Cited by 91 · see citing works
Metabolism in the Tumor Microenvironment
Lau, A. N., & Heiden, M. G. V. (2019) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033333 · Cited by 89 · see citing works
Multi‑faceted role of cancer‑associated adipocytes in the tumor microenvironment (Review)
Yao, H., & He, S. (2021) · Molecular Medicine Reports · doi:10.3892/mmr.2021.12506 · Cited by 88 · see citing works
Emerging mechanisms and promising approaches in pancreatic cancer metabolism
Wu, H., Fu, M., Wu, M., Cao, Z., Zhang, Q., & Liu, Z. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06930-0 · Cited by 87 · see citing works
Halbrook, C. J., Thurston, G., Boyer, S., Anaraki, C., Jiménez, J. A., McCarthy, A., Steele, N. G., Kerk, S. A., Hong, H. S., Lin, L., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00463-1 · Cited by 80 · see citing works
Self-citationMatas-Rico, E., Frijlink, E., Àvila, I. V. D. H., Menegakis, A., van Zon, M., Morris, A. J., Köster, J., Salgado-Polo, F., de Kivit, S., Lança, T., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110013 · Cited by 80 · see citing works
The fibrotic and immune microenvironments as targetable drivers of metastasis
Boulter, L., Bullock, E., Mabruk, Z., & Brunton, V. G. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-01172-1 · Cited by 78 · see citing works
Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis
Saab, J. J. A., Dzierozynski, L. N., Jonker, P. B., AminiTabrizi, R., Shah, H., Menjivar, R. E., Scott, A. J., Nwosu, Z. C., Zhu, Z., Chen, R. N., et al. (2023) · eLife · doi:10.7554/elife.81289 · Cited by 80 · see citing works
Qiu, Y., Wang, X., Sun, Y., Jin, T., Tang, R., Zhou, X., Xu, M., Gan, Y., Wang, R., Luo, H., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-2491 · Cited by 78 · see citing works
Fibroblasts as Modulators of Local and Systemic Cancer Metabolism
Sanford-Crane, H., Abrego, J., & Sherman, M. H. (2019) · Cancers · doi:10.3390/cancers11050619 · Cited by 77 · see citing works
Self-citationThe Interplay of the Extracellular Matrix and Stromal Cells as a Drug Target in Stroma-Rich Cancers
Kozlova, N., Grossman, J. E., Iwanicki, M. P., & Muranen, T. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.01.001 · Cited by 73 · see citing works
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 76 · see citing works
Deregulated Lysophosphatidic Acid Metabolism and Signaling in Liver Cancer
Kaffe, E., Magkrioti, C., & Aidinis, V. (2019) · Cancers · doi:10.3390/cancers11111626 · Cited by 73 · see citing works
Leroux, C., & Konstantinidou, G. (2021) · Cancers · doi:10.3390/cancers13040799 · Cited by 76 · see citing works
Tumor microenvironmental nutrients, cellular responses, and cancer
Lobel, G. P., Jiang, Y., & Simon, M. C. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.08.011 · Cited by 74 · see citing works
Spatial adaptation of eosinophils and their emerging roles in homeostasis, infection and disease
Arnold, I. C., & Munitz, A. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-01048-y · Cited by 76 · see citing works
Latest Advances in Targeting the Tumor Microenvironment for Tumor Suppression
Laplagne, C., Domagala, M., Naour, A. L., Quémerais, C., Hamel, D., Fournié, J., Couderc, B. C., Bousquet, C., Ferrand, A., & Poupot, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194719 · Cited by 73 · see citing works
Targeting cancer metabolic pathways for improving chemotherapy and immunotherapy
Luo, Z., Eichinger, K. M., Zhang, A., & Li, S. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216396 · Cited by 70 · see citing works
New dawn for cancer cell death: Emerging role of lipid metabolism
Zhang, C., Zhu, N., Li, H., Gong, Y.-Z., Gu, J., Shi, Y., Liao, D., Wang, W., Dai, A., & Li, Q. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101529 · Cited by 65 · see citing works
Li, F., He, C., Yao, H., Zhao, Y., Ye, X., Zhou, S., Zou, J., Li, Y., Li, J., Chen, S., et al. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106555 · Cited by 69 · see citing works
ACSL3–PAI-1 signaling axis mediates tumor-stroma cross-talk promoting pancreatic cancer progression
Sebastiano, M. R., Pozzato, C., Saliakoura, M., Zhang, Y., Peng, R., Galiè, M., Oberson, K., Simon, H., Karamitopoulou, E., & Konstantinidou, G. (2020) · Science Advances · doi:10.1126/sciadv.abb9200 · Cited by 68 · see citing works
Potential mechanisms of cancer-associated fibroblasts in therapeutic resistance
Zhao, Z., Li, T., Sun, L. L., Yuan, Y., & Zhu, Y. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115425 · Cited by 68 · see citing works
Radiotherapy-induced metabolic hallmarks in the tumor microenvironment
Mittal, A., Nenwani, M., Sarangi, I., Achreja, A., Lawrence, T. S., & Nagrath, D. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.05.005 · Cited by 69 · see citing works
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 69 · see citing works
Lee‐Rueckert, M., Canyelles, M., Tondo, M., Rotllán, N., Kovanen, P. T., Llorente‐Cortés, V., & Escolá‐Gil, J. C. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.05.002 · Cited by 68 · see citing works
Reprogramming of lipid metabolism in the tumor microenvironment: a strategy for tumor immunotherapy
Wu, Y., Pu, X., Wang, X., & Xu, M. (2024) · Lipids in Health and Disease · doi:10.1186/s12944-024-02024-0 · Cited by 66 · see citing works
Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer
Chae, C.-S., Sandoval, T. A., Hwang, S., Park, E. S., Giovanelli, P., Awasthi, D., Salvagno, C., Emmanuelli, A., Tan, C., Chaudhary, V., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1181 · Cited by 64 · see citing works
Intrapancreatic fat, pancreatitis, and pancreatic cancer
Lilly, A. C., Astsaturov, I. A., & Golemis, E. A. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04855-z · Cited by 59 · see citing works
The tumor microenvironment is an ecosystem sustained by metabolic interactions
Kay, E. J., & Zanivan, S. R. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115432 · Cited by 60 · see citing works
A Cancer Cell–Intrinsic GOT2–PPARδ Axis Suppresses Antitumor Immunity
Abrego, J., Sanford-Crane, H. S., Oon, C. H., Xu, X., Betts, C. B., Sun, D., Nagarajan, S., Diaz, L. F., Sandborg, H., Bhattacharyya, S., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0661 · Cited by 59 · see citing works
Self-citationThe interactive role of inflammatory mediators and metabolic reprogramming in pancreatic cancer
Ohara, Y., Valenzuela, P., & Hussain, S. P. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.03.004 · Cited by 53 · see citing works
Chen, H., Zhang, Y., Wu, C., & Huang, Q. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01428-8 · Cited by 58 · see citing works
Lipid Phosphate Phosphatases and Cancer
Tang, X., & Brindley, D. N. (2020) · Biomolecules · doi:10.3390/biom10091263 · Cited by 54 · see citing works
Pancreatic Cancer and Its Microenvironment—Recent Advances and Current Controversies
Stopa, K. B., Kusiak, A. A., Szopa, M. D., Ferdek, P. E., & Jakubowska, M. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093218 · Cited by 54 · see citing works
Targeting cancer-associated fibroblasts: Challenges, opportunities and future directions
Jenkins, B. H., Buckingham, J. F., Hanley, C. J., & Thomas, G. J. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108231 · Cited by 52 · see citing works
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 · see citing works
Kesh, K., Garrido, V. T., Dosch, A. R., Durden, B. C., Gupta, V. K., Sharma, N., Lyle, M. P. A., Nagathihalli, N. S., Merchant, N. B., Saluja, A. K., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03168-4 · Cited by 50 · see citing works
Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective
Gentric, G., & Mechta‐Grigoriou, F. (2021) · Cancers · doi:10.3390/cancers13030399 · Cited by 50 · see citing works
Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition
Yan, L., Tu, B., Yao, J., Gong, J., Carugo, A., Bristow, C. A., Wang, Q., Zhu, C., Dai, B., Kang, Y., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3792 · Cited by 48 · see citing works
Targeting the Metabolic Rewiring in Pancreatic Cancer and Its Tumor Microenvironment
Yamamoto, K., Iwadate, D., Kato, H., Nakai, Y., Tateishi, K., & Fujishiro, M. (2022) · Cancers · doi:10.3390/cancers14184351 · Cited by 48 · see citing works
Statins as anti‐tumor agents: A paradigm for repurposed drugs
Tripathi, S., Gupta, E., & Galande, S. (2024) · Cancer Reports · doi:10.1002/cnr2.2078 · Cited by 50 · see citing works
Vishwa, R., BharathwajChetty, B., Girisa, S., Aswani, B. S., Alqahtani, M. S., Abbas, M. A. E., Hegde, M., & Kunnumakkara, A. B. (2024) · Cancer and Metastasis Reviews · doi:10.1007/s10555-024-10170-1 · Cited by 47 · see citing works
Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment
Low, V., Li, Z., & Blenis, J. (2022) · Science Signaling · doi:10.1126/scisignal.abj4220 · Cited by 44 · see citing works
Bhattacharyya, S., Oon, C. H., Diaz, L. F., Sandborg, H., Stempinski, E., Saoi, M., Morgan, T. K., López, C. S., Cross, J. R., & Sherman, M. H. (2024) · Nature Cancer · doi:10.1038/s43018-023-00703-y · Cited by 43 · see citing works
Self-citationUnraveling the intricate relationship between lipid metabolism and oncogenic signaling pathways
Khan, F., Elsori, D. H., Verma, M., Pandey, S., Rab, S. O., Siddiqui, S., Alabdallah, N. M., Saeed, M., & Pandey, P. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1399065 · Cited by 44 · see citing works
Deconstructing tumor heterogeneity: the stromal perspective
Vickman, R. E., Faget, D. V., Beachy, P. A., Beebe, D. J., Bhowmick, N. A., Cukierman, E., Deng, W.-M., Granneman, J. G., Hildesheim, J., Kalluri, R., et al. (2020) · Oncotarget · doi:10.18632/oncotarget.27736 · Cited by 43 · see citing works
Self-citationMetabolites and Immune Response in Tumor Microenvironments
Cortellino, S., & Longo, V. D. (2023) · Cancers · doi:10.3390/cancers15153898 · Cited by 42 · see citing works
- Authors
- Auciello, F. R., Bulusu, V., Oon, C., Tait-Mulder, J., Berry, M., Bhattacharyya, S., Tumanov, S., Allen-Petersen, B. L., Link, J., Kendsersky, N. D., Vringer, E., Schug, M., Novo, D., Hwang, R. F., Evans, R. M., Nixon, C., Dorrell, C., Morton, J. P., Norman, J. C., Sears, R. C., Kamphorst, J. J., & Sherman, M. H.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Oregon Health & Science University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Kamphorst, Jurre J.
- Sherman, Mara H.
- ORCID
- Auciello, Francesca R.
- Bulusu, Vinay
- Oon, Chet
- Tait-Mulder, Jacqueline
- Bhattacharyya, Sohinee
- Tumanov, Sergey
- Allen-Petersen, Brittany L.
- Link, Jason
- Kendsersky, Nicholas D.
- Vringer, Esmee
- Novo, David
- Hwang, Rosa F.
- Evans, Ronald M.
- Nixon, Colin
- Dorrell, Craig
- Morton, Jennifer P.
- Norman, Jim C.
- Sears, Rosalie C.
- Kamphorst, Jurre J.
- Sherman, Mara H.
- Venue
- Cancer Discovery
- Published
- 2019-05-01
- Volume
- 9
- Issue
- 5
- Pages
- 617-627
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6497553
- OpenAlex
- W2920517824
- Cited by
- 332
- References
- 32
- Citations by year
- 2026: 35 · 2025: 34 · 2024: 61 · 2023: 56 · 2022: 50 · 2021: 38 · 2020: 49 · 2019: 9
- FWCI
- 12.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Funders
- Cancer Research UK (C596/A18076, C596/A17196, C50242/A17728)
- National Cancer Institute (CA188259-01, R01CA229580)
- V Foundation (V2017-009)
- American Cancer Society (132898-RSG-18-142-01-CSM)
- Hirshberg Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, pancreatic stellate cells, autotaxin, lysophosphatidic acid, lysophosphatidylcholine, tumor stroma, cancer-associated fibroblasts, lipid metabolism, phosphatidylcholine synthesis, Akt activation, cell proliferation and migration
- MeSH terms
- Lysophospholipase D, Animals, Cell Movement, Disease Models, Animal, Female, Humans, Lysophosphatidylcholines, Male, Mice, Inbred C57BL, Mice, Nude, Pancreatic Neoplasms, Phosphoric Diester Hydrolases, Tumor Cells, Cultured, Signal Transduction, Stromal Cells, Disease Progression, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Proliferation, Pancreatic Stellate 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
