Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma

Diogo Maia-Silva; Patrick J. Cunniff; Allison C. Schier; Damianos Skopelitis; Marygrace C. Trousdell; Philip Moresco; Yuan Gao; Vahag Kechejian; Xue Yan He; Yunus Sahin; Ledong Wan; Aktan Alpsoy; Jynelle Liverpool; Adrian R. Krainer; Mikala Egeblad; David L. Spector; Douglas T. Fearon; Camila O. dos Santos; Dylan J. Taatjes; Christopher R. Vakoc

doi:10.1038/s41588-024-01790-y

Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma

Diogo Maia-Silva, Patrick J. Cunniff, Allison C. Schier, Damianos Skopelitis, Marygrace C. Trousdell, Philip Moresco, Yuan Gao, Vahag Kechejian, Xue Yan He, Yunus Sahin, Ledong Wan, Aktan Alpsoy, Jynelle Liverpool, Adrian R. Krainer, Mikala Egeblad, David L. Spector, Douglas T. Fearon, Camila O. dos Santos, Dylan J. Taatjes, Christopher R. Vakoc

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Abstract

The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.

Original language	English
Pages (from-to)	1377-1385
Number of pages	9
Journal	Nature Genetics
Volume	56
Issue number	7
DOIs	https://doi.org/10.1038/s41588-024-01790-y
State	Published - Jul 2024

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Maia-Silva, D., Cunniff, P. J., Schier, A. C., Skopelitis, D., Trousdell, M. C., Moresco, P., Gao, Y., Kechejian, V., He, X. Y., Sahin, Y., Wan, L., Alpsoy, A., Liverpool, J., Krainer, A. R., Egeblad, M., Spector, D. L., Fearon, D. T., dos Santos, C. O., Taatjes, D. J., & Vakoc, C. R. (2024). Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma. Nature Genetics, 56(7), 1377-1385. https://doi.org/10.1038/s41588-024-01790-y

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title = "Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma",

abstract = "The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.",

author = "Diogo Maia-Silva and Cunniff, {Patrick J.} and Schier, {Allison C.} and Damianos Skopelitis and Trousdell, {Marygrace C.} and Philip Moresco and Yuan Gao and Vahag Kechejian and He, {Xue Yan} and Yunus Sahin and Ledong Wan and Aktan Alpsoy and Jynelle Liverpool and Krainer, {Adrian R.} and Mikala Egeblad and Spector, {David L.} and Fearon, {Douglas T.} and {dos Santos}, {Camila O.} and Taatjes, {Dylan J.} and Vakoc, {Christopher R.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = jul,

doi = "10.1038/s41588-024-01790-y",

language = "English",

volume = "56",

pages = "1377--1385",

journal = "Nature Genetics",

issn = "1061-4036",

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Maia-Silva, D, Cunniff, PJ, Schier, AC, Skopelitis, D, Trousdell, MC, Moresco, P, Gao, Y, Kechejian, V, He, XY, Sahin, Y, Wan, L, Alpsoy, A, Liverpool, J, Krainer, AR, Egeblad, M, Spector, DL, Fearon, DT, dos Santos, CO, Taatjes, DJ & Vakoc, CR 2024, 'Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma', Nature Genetics, vol. 56, no. 7, pp. 1377-1385. https://doi.org/10.1038/s41588-024-01790-y

TY - JOUR

T1 - Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma

AU - Maia-Silva, Diogo

AU - Cunniff, Patrick J.

AU - Schier, Allison C.

AU - Skopelitis, Damianos

AU - Trousdell, Marygrace C.

AU - Moresco, Philip

AU - Gao, Yuan

AU - Kechejian, Vahag

AU - He, Xue Yan

AU - Sahin, Yunus

AU - Wan, Ledong

AU - Alpsoy, Aktan

AU - Liverpool, Jynelle

AU - Krainer, Adrian R.

AU - Egeblad, Mikala

AU - Spector, David L.

AU - Fearon, Douglas T.

AU - dos Santos, Camila O.

AU - Taatjes, Dylan J.

AU - Vakoc, Christopher R.

PY - 2024/7

Y1 - 2024/7

N2 - The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.

AB - The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.

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U2 - 10.1038/s41588-024-01790-y

DO - 10.1038/s41588-024-01790-y

M3 - Letter

C2 - 38886586

AN - SCOPUS:85196212477

SN - 1061-4036

VL - 56

SP - 1377

EP - 1385

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma

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