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MAPK Signaling Is Required for Dedifferentiation of Acinar Cells and Development of Pancreatic Intraepithelial Neoplasia in Mice
Open accessAbstract
Background & aims Kras signaling via mitogen-activated protein kinase (MAPK) is highly up-regulated in pancreatic cancer cells. We investigated whether MAPK signaling is required for the initiation and maintenance of pancreatic carcinogenesis in mice.Methods We studied the formation and maintenance of pancreatic intraepithelial neoplasia (PanINs) in p48Cre; TetO-KrasG12D; Rosa26(rtTa-IRES-EGFP) (iKras*) mice and LSL-KrasG12D mice bred with p48Cre mice (KC). Mice were given oral PD325901, a small-molecule inhibitor of MEK1 and MEK2 (factors in the MAPK signaling pathway), along with injections of cerulein to induce pancreatitis. Other mice were given PD325901 only after PanINs developed. Pancreatic tissues were collected and evaluated using histologic, immunohistochemical, immunofluorescence, and electron microscopy analyses. Acinar cells were isolated from the tissues and the effects of MEK1 and 2 inhibitors were assessed.Results PD325901 prevented PanIN formation, but not pancreatitis, in iKras* and KC mice. In iKras* or KC mice given PD325901 at 5 weeks after PanINs developed, PanINs regressed and acinar tissue regenerated. The regression occurred through differentiation of the PanIN cells to acini, accompanied by re-expression of the acinar transcription factor Mist1.Conclusions In iKras* and KC mice, MAPK signaling is required for the initiation and maintenance of pancreatic cancer precursor lesions. MAPK signaling promotes formation of PanINs by enabling dedifferentiation of acinar cells into duct-like cells that are susceptible to transformation.
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“in such an inducible system, PanINs can be observed to re-differentiate back to acinar cells in the absence of tumor suppressor loss66.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [66]
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State of the art and future directions of pancreatic ductal adenocarcinoma therapy
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“Indeed, work from the Pasca di Magliano Lab (Collins et al., 2012, 2014) has shown that precancerous PDAC lesions exhibit plasticity and can be reverted back to healthy pancreatic acinar tissue upon loss of oncogenic KRAS signaling.”
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The Integrated Stress Response in Pancreatic Development, Tissue Homeostasis, and Cancer
Malnassy, G., Ziolkowski, L. M., Macleod, K. F., & Oakes, S. A. (2024) · Gastroenterology · doi:10.1053/j.gastro.2024.05.009 · Cited by 22
Beta 1 integrin signaling mediates pancreatic ductal adenocarcinoma resistance to MEK inhibition
Brannon, A., Drouillard, D., Steele, N. G., Schoettle, S., Abel, E. V., Crawford, H. C., & di Magliano, M. P. (2020) · Scientific Reports · doi:10.1038/s41598-020-67814-9 · Cited by 19
Das, K. K., & Early, D. S. (2017) · Current Treatment Options in Gastroenterology · doi:10.1007/s11938-017-0149-8 · Cited by 19
Zhang, X., Du, Y., Behrens, A., & Lan, L. (2025) · Developmental Cell · doi:10.1016/j.devcel.2025.07.002 · Cited by 19
Wang, C.-A., Li, C., Huang, R.-C., Li, Y.-H., Liou, J., & Tsai, S. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0963 · Cited by 18
ELAPOR1 is a secretory granule maturation-promoting factor that is lost during paligenosis
Cho, C. J., Park, D., & Mills, J. C. (2021) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00246.2021 · Cited by 18
Method for improved integrity of RNA isolated from Matrigel cultures
Silva, L. D., Bray, J. K., Bulut, G. B., Jiang, J., & Schmittgen, T. D. (2020) · MethodsX · doi:10.1016/j.mex.2020.100966 · Cited by 18
Transcriptional Profile of Human Pancreatic Acinar Ductal Metaplasia
Jiang, J., Hakimjavadi, H., Bray, J. K., Perkins, C. M., Gosling, A., daSilva, L., Bulut, G. B., Ali, J., Setiawan, V. W., Campbell‐Thompson, M., et al. (2023) · Gastro Hep Advances · doi:10.1016/j.gastha.2023.02.003 · Cited by 17
The secret origins and surprising fates of pancreas tumors
Bailey, J. M., DelGiorno, K. E., & Crawford, H. C. (2014) · Carcinogenesis · doi:10.1093/carcin/bgu056 · Cited by 17
“(64), who showed that inhibition of MEK, a downstream target of Kras*, leads to regression of early mPanIN by forcing redifferentiation of the neoplasia to acinar cells.”
BackgroundHuang, X., Bhugul, P. A., Fan, G., Ye, T., Huang, S., Dai, S., Chen, B., & Zhou, M. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.8327 · Cited by 17
“Also, the downward pathways of EGFR, such as mitogen-activated protein kinase signaling and phosphatidyl inositol 3-kinase signaling, are required for PanIN formation and pancreatic carcinogenesis (13,14).”
Targeting ribosome biogenesis reinforces ERK-dependent senescence in pancreatic cancer
Rowell, M., Deschênes‐Simard, X., Lopes‐Paciencia, S., Calvé, B. L., Kalegari, P., Mignacca, L., Ruiz, A. F., Guillon, J., Lessard, F., Bourdeau, V., et al. (2023) · Cell Cycle · doi:10.1080/15384101.2023.2278945 · Cited by 16
“This is consistent with a proposed role for ERK activation in the ded-ifferentiation of acinar cells during ADM [16].”
BackgroundLoss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury
Bray, J. K., Elgamal, O. A., Jiang, J., Wright, L. S., Sutaria, D. S., Badawi, M. A., Borcyk, M. G., Liu, X., Fredenburg, K. M., Campbell‐Thompson, M., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2269-7 · Cited by 16
Bangs, F. K., Miller, P. F., & O’Neill, E. E. (2020) · Disease Models & Mechanisms · doi:10.1242/dmm.044289 · Cited by 16
Deletion of Histone Methyltransferase G9a Suppresses Mutant Kras-driven Pancreatic Carcinogenesis
Kato, H., Tateishi, K., Fujiwara, H., Ijichi, H., Yamamoto, K., Nakatsuka, T., Kakiuchi, M., Sano, M., Kudo, Y., Hayakawa, Y., et al. (2020) · Cancer Genomics & Proteomics · doi:10.21873/cgp.20224 · Cited by 16
Döppler, H. R., Liou, G., & Störz, P. (2022) · Antioxidants · doi:10.3390/antiox11010137 · Cited by 16
The Role of Krüppel-like Factors in Pancreatic Physiology and Pathophysiology
Giarrizzo, M., LaComb, J. F., & Bialkowska, A. B. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24108589 · Cited by 14
Tao, X., Xiang, H., Pan, Y., Shang, D., Guo, J., Gao, G., & Xiao, G. G. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105595 · Cited by 13
Novel strategy for oncogenic alteration-induced lipid metabolism reprogramming in pancreatic cancer
Guo, D., Ye, L., Wu, W., Yu, X., & Jin, K. (2023) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2023045 · Cited by 13
“Furthermore, the MAPK signaling pathway was proven to be required for the formation of PanINs in mice because it promotes the dedifferentiation of acinar cells into duct-like cells, which are easily transformed [37].”
Fey, S. K., Najumudeen, A. K., Watt, D. M., Millett, L. M., Ford, C. A., Gilroy, K. L., Simpson, R. J., McLay, K., Upstill‐Goddard, R., Chang, D. K.-F., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-2709 · Cited by 11
“Given the increased PanIN burden and MAPK signaling in the pancreata of KC Kras G12D/fl mice, we determined whether these PanIN lesions were sensitive to therapeutic targeting of the MAPK pathway, as has previously been reported in KC Kras G12D/+ mice (29, 30).”
Murine Models of Pancreatitis Leading to the Development of Pancreatic Cancer
Leal, A. S., & Liby, K. T. (2018) · Current Protocols in Pharmacology · doi:10.1002/cpph.48 · Cited by 11
Zhu, Y., Zhang, C., Zhao, D., Li, W., Zhao, Z., Yao, S., & Zhao, D. (2021) · Disease Markers · doi:10.1155/2021/7842035 · Cited by 11
“RAS-stimulated signaling of MAPK has been reported to be tightly activated in pancreatic cancer, responsible for the initiation and maintenance of pancreatic carcinogenesis [48].”
BackgroundETV5 regulates ductal morphogenesis with Sox9 and is critical for regeneration from pancreatitis
Das, K. K., Heeg, S., Pitarresi, J. R., Reichert, M., Bakir, B. S., Takano, S., Kopp, J. L., Wahl‐Feuerstein, A., Hicks, P. D., Sander, M., et al. (2018) · Developmental Dynamics · doi:10.1002/dvdy.24626 · Cited by 10
“In addition to a ductal morphology, ADM cells co-express acinar and ductal markers and exhibit up-regulation of signaling pathways such as epidermal growth factor receptor (EGFR) and NOTCH, and downstream effectors such as the KRASMEK-MAPK pathway, which are increased during pancreatic tumorigenesis (Miyamoto et al.,…”
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
Srinivasan, S., Mehra, S., Jinka, S., Bianchi, A., Singh, S. P., Dosch, A. R., Amirian, H., Krishnamoorthy, V., Silva, I. D. C., Patel, M. S., et al. (2025) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2025.101606 · Cited by 9
“10,11 12–14 Building on our lab’s long standing efforts in understanding the multifaceted role of transcription factor signaling in pancreatitis and pancreatic cancer, we have previously identified hyperactivation of cyclic adenosine monophosphate response element-binding protein 1 (CREB) via…”
Clinical significance of pancreatic ductal metaplasia
Jiang, T., Fang, W., & Xie, K. (2022) · The Journal of Pathology · doi:10.1002/path.5883 · Cited by 8
“Likewise, PDM could be formed by the reversal of PanIN, given the plasticity of PanIN [101].”
BackgroundInfluentialJing, T., Xu, X., Wu, C., Wei, D., Yuan, L., Huang, Y., Liu, Y., & Wang, B. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216444 · Cited by 8
Murugesan, P., Begum, H., & Tangutur, A. D. (2022) · Gene · doi:10.1016/j.gene.2022.147092 · Cited by 8
Kiemen, A. L., Almagro-Pérez, C., Matos, V., Forjaz, A., Braxton, A. M., Dequiedt, L., Parksong, J., Cannon, C. D., Yuan, X., Shin, S. M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.03.606493 · Cited by 8
Hu, J., Jiang, J., Xu, B., Li, Y., Wang, B., He, S., Ren, X., Shi, B., Zhang, X., Zheng, H., et al. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117590 · Cited by 6
Li, X., He, J., & Xie, K. (2022) · Cellular Oncology · doi:10.1007/s13402-022-00664-x · Cited by 6
“Alternatively, PDM may be formed by the reversal of PanIN, given the plasticity of PanIN [77].”
BackgroundInfluentialWaldron, R. T. (2015) · doi:10.3998/panc.2015.41 · Cited by 6
Inflammation and de-differentiation in pancreatic carcinogenesis
Seimiya, T., Otsuka, M., Iwata, T., Tanaka, E., Suzuki, T., Sekiba, K., Yamagami, M., Ishibashi, R., & Koike, K. (2018) · World Journal of Clinical Cases · doi:10.12998/wjcc.v6.i15.882 · Cited by 5
Metabolism Drives Carcinogenesis and Maintenance of Pancreatic Tumors
Halbrook, C. J., Nelson, B. S., & Lyssiotis, C. A. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0034 · Cited by 5
Exome Sequencing of Pancreatic Acinar Carcinoma Identified Distinctive Mutation Patterns
Liu, Y., Raimondo, M., Wallace, M. B., Mody, K., Stauffer, J. A., Zhang, L., Ji, B., & Bi, Y. (2021) · Pancreas · doi:10.1097/mpa.0000000000001870 · Cited by 5
“In ACC, the MAPK pathway is also critical for acinar cell physiologic function and maintains its differentiation.(54) Comprehensive genomic analysis showed that approximately 23% of ACC tumors had recurrent rearrangement involving BRAF and RAF1, resulting in MAPK pathway activation, which can be abrogated by theMAPK k…”
BackgroundOncogenic KRAS, Mucin 4, and Activin A‐Mediated Fibroblast Activation Cooperate for PanIN Initiation
Hu, C., Huang, C., Hsu, M., Chien, H., Wu, P., Chen, Y., Jeng, Y., Tang, S., Chung, M., Shen, C., et al. (2023) · Advanced Science · doi:10.1002/advs.202301240 · Cited by 5
Stabilization of HIF-2α impacts pancreas growth
Flores‐Martínez, Á., García-Núñez, A., Rojas, A., & Cano, D. A. (2018) · Scientific Reports · doi:10.1038/s41598-018-32054-5 · Cited by 5
MAPK Signaling and the Tumor Microenvironment: Drivers of Cancer Development and Resistance
Owida, H. A., Mohammad, S. I., Patel, P. N., Roopashree, R., Vasudevan, A., Arora, V., Nayak, P. P., Shukla, S. K., Hjazi, A. M., & Hsu, C.-Y. (2026) · DNA and Cell Biology · doi:10.1177/10445498261417426 · Cited by 4
“Inhibition of MAPK signaling has been shown to partially rescue aspects of dedifferentiation by rep-rioritizing acinar cell differentiation back (Collins et al., 2014).”
Yang, H.-J., Song, B., Sim, B., Jung, Y., Chae, U., Lee, D. G., Cha, J., Baek, S.-J., Lim, K. S., Choi, W. S., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228820 · Cited by 4
“Therefore, the importance of the MAPK signaling pathway is supported by its promotion of PanIN, which renders ADM susceptible to transformation [40].”
BackgroundSavary, C., Picard, C., Corradini, N., & Castets, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116310 · Cited by 5
Juin, A., Spence, H. J., & Machesky, L. M. (2024) · The Journal of Pathology · doi:10.1002/path.6248 · Cited by 4
“To identify the mechanisms by which MAP4K4 drives PDAC tumorigenesis, we investigated the functional interplay between MAP4K4 and signalling pathways frequently activated during pancreatic intraepithelial neoplasia development [10,37,39].”
BackgroundOncogenic KRAS/ERK/JUNB signaling suppresses differentiation regulator GATA6 in pancreatic cancer
Zhong, Z., Cao, X., Liao, P.-J., Sethi, R., Klomp, J. A., Stalnecker, C. A., Chen, J., Wan, Y., Der, C. J., & Virshup, D. M. (2025) · Journal of Clinical Investigation · doi:10.1172/jci191370 · Cited by 3
Wei, F., Zou, Q., An, J., Zhang, T., Sun, Q., Li, X., Jiang, T., Zhu, X., Wen, T., He, J., et al. (2026) · Gastroenterology · doi:10.1053/j.gastro.2026.02.033 · Cited by 4
Metadata
- Authors
- Collins, M. A., Yan, W., Sebolt–Leopold, J. S., & Pasca di Magliano, M.
- Affiliations
- University of Michigan (US)
- ORCID
- Yan, Wei
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 146
- Issue
- 3
- Pages
- 822-834.e7
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC4037403
- OpenAlex
- W2010171965
- Cited by
- 133
- References
- 46
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 8 · 2023: 19 · 2022: 12 · 2021: 11 · 2020: 15 · 2019: 6 · 2018: 14 · 2017: 11 · 2016: 8 · 2015: 11 · 2014: 3
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA151588, P50CA130810, R01CA155198, P50CA13810)
- National Institute of General Medical Sciences (T32GM07315, T32GM007315)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (5-T32-HD007515, T32HD007505)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- MAPK signaling, pancreatic intraepithelial neoplasia, KRAS G12D, pancreatic carcinogenesis, MEK1/2 inhibition, pancreatitis, Mist1, pancreatic cancer precursor lesions
- MeSH terms
- Animals, Carcinoma in Situ, Disease Models, Animal, Female, Male, Mice, Mutant Strains, Pancreatic Neoplasms, Pancreatitis, Signal Transduction, Up-Regulation, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Mice, Cell Dedifferentiation, Acinar Cells
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