Oncogenic KRAS, Mucin 4, and Activin A‐Mediated Fibroblast Activation Cooperate for PanIN Initiation

Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN format...

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Published inAdvanced science Vol. 10; no. 36; pp. e2301240 - n/a
Main Authors Hu, Chun‐Mei, Huang, Chien‐Chang, Hsu, Min‐Fen, Chien, Hung‐Jen, Wu, Pei‐Jung, Chen, Yi‐Ing, Jeng, Yung‐Ming, Tang, Shiue‐Cheng, Chung, Mei‐Hsin, Shen, Chia‐Ning, Chang, Ming‐Chu, Chang, Yu‐Ting, Tien, Yu‐Wen, Lee, Wen‐Hwa
Format Journal Article
LanguageEnglish
Published Germany John Wiley & Sons, Inc 01.12.2023
John Wiley and Sons Inc
Wiley
Subjects
activin A
Animals
Carcinoma in Situ - genetics
Carcinoma in Situ - pathology
Carcinoma, Pancreatic Ductal - genetics
Fibroblasts
Genes
Genomes
Humans
Kras
Metastasis
Mice
Mice, Transgenic
Muc4
Mucin-4
Mutation
Pancreatic cancer
Pancreatic Neoplasms - genetics
PanIN
Proto-Oncogene Proteins p21(ras) - genetics
Transgenic animals
αSMA+ fibroblast
αSMA+ fibroblast
Kras
Muc4
PanIN
activin A
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Abstract Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic‐clear 3D histology is used to analyze entire pancreases of 2‐week‐old Pdx1‐Cre; LSL‐KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN‐associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+‐driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches. This study found that early PanIN cells express elevated levels of Muc4, specifically the oncogenic Muc4/X variant, and are closely associated with αSMA+ fibroblasts. This is observed in KrasG12D/+ transgenic mice and human pancreatic specimens with early PanINs. Importantly, upregulated Muc4 expression and Activin A secretion are identified as critical factors driving PanIN initiation in pancreatic cells with KrasG12D/+ mutation.
AbstractList Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic‐clear 3D histology is used to analyze entire pancreases of 2‐week‐old Pdx1‐Cre; LSL‐KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN‐associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+‐driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches. This study found that early PanIN cells express elevated levels of Muc4, specifically the oncogenic Muc4/X variant, and are closely associated with αSMA+ fibroblasts. This is observed in KrasG12D/+ transgenic mice and human pancreatic specimens with early PanINs. Importantly, upregulated Muc4 expression and Activin A secretion are identified as critical factors driving PanIN initiation in pancreatic cells with KrasG12D/+ mutation.
Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic‐clear 3D histology is used to analyze entire pancreases of 2‐week‐old Pdx1 ‐ Cre ; LSL ‐ Kras G12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA + fibroblasts in both transgenic mice and human specimens. Mechanistically, Kras G12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN‐associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic Kras G12D/+ ‐driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches. This study found that early PanIN cells express elevated levels of Muc4, specifically the oncogenic Muc4/X variant, and are closely associated with αSMA+ fibroblasts. This is observed in Kras G12D/+ transgenic mice and human pancreatic specimens with early PanINs. Importantly, upregulated Muc4 expression and Activin A secretion are identified as critical factors driving PanIN initiation in pancreatic cells with Kras G12D/+ mutation.
Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-Kras (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA fibroblasts in both transgenic mice and human specimens. Mechanistically, Kras pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic Kras -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.
Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+-driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.
Abstract Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic‐clear 3D histology is used to analyze entire pancreases of 2‐week‐old Pdx1‐Cre; LSL‐KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN‐associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+‐driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.
Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic‐clear 3D histology is used to analyze entire pancreases of 2‐week‐old Pdx1 ‐ Cre ; LSL ‐ Kras G12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA + fibroblasts in both transgenic mice and human specimens. Mechanistically, Kras G12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN‐associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic Kras G12D/+ ‐driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.
Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.
Author Chang, Yu‐Ting
Jeng, Yung‐Ming
Huang, Chien‐Chang
Chien, Hung‐Jen
Tien, Yu‐Wen
Hsu, Min‐Fen
Hu, Chun‐Mei
Chang, Ming‐Chu
Lee, Wen‐Hwa
Chung, Mei‐Hsin
Wu, Pei‐Jung
Chen, Yi‐Ing
Shen, Chia‐Ning
Tang, Shiue‐Cheng
AuthorAffiliation 6 Department of Pathology National Taiwan University Hospital−Hsinchu Branch Hsinchu 30331 Taiwan
3 Department of Pathology National Taiwan University Hospital Taipei 10041 Taiwan
1 Genomics Research Center Academia Sinica Taipei 11529 Taiwan
5 Department of Medical Science National Tsing Hua University Hsinchu 30013 Taiwan
7 Department of Internal Medicine National Taiwan University Hospital Taipei 10041 Taiwan
2 Biomedical Translation Research Center Academia Sinica Taipei 11529 Taiwan
8 Department of Surgery National Taiwan University Hospital Taipei 10041 Taiwan
10 Department of Biological Chemistry University of California Irvine CA 92697 USA
4 Graduate Institute of Pathology, College of Medicine National Taiwan University Taipei 10041 Taiwan
9 Drug Development Center China Medical University Taichung 40402 Taiwan
AuthorAffiliation_xml – name: 3 Department of Pathology National Taiwan University Hospital Taipei 10041 Taiwan
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/37964407$$D View this record in MEDLINE/PubMed
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CitedBy_id crossref_primary_10_1080_13880209_2024_2421759
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IsDoiOpenAccess true
IsOpenAccess true
IsPeerReviewed true
IsScholarly true
Issue 36
Keywords αSMA+ fibroblast
Kras
Muc4
PanIN
activin A
Language English
License Attribution
2023 The Authors. Advanced Science published by Wiley-VCH GmbH.
This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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SSID ssj0001537418
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Snippet Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate...
Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate...
Abstract Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to...
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StartPage e2301240
SubjectTerms activin A
Animals
Carcinoma in Situ - genetics
Carcinoma in Situ - pathology
Carcinoma, Pancreatic Ductal - genetics
Fibroblasts
Genes
Genomes
Humans
Kras
Metastasis
Mice
Mice, Transgenic
Muc4
Mucin-4
Mutation
Pancreatic cancer
Pancreatic Neoplasms - genetics
PanIN
Proto-Oncogene Proteins p21(ras) - genetics
Transgenic animals
αSMA+ fibroblast
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Title Oncogenic KRAS, Mucin 4, and Activin A‐Mediated Fibroblast Activation Cooperate for PanIN Initiation
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fadvs.202301240
https://www.ncbi.nlm.nih.gov/pubmed/37964407
https://www.proquest.com/docview/2906768633
https://www.proquest.com/docview/2890362586
https://pubmed.ncbi.nlm.nih.gov/PMC10754145
https://doaj.org/article/4a0e87c67012457eb7ccce5aa913ffd6
Volume 10
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