A KRT17/GATA6 hybrid state marks unique vulnerability to MYC in pancreatic cancer
Abstract
Pancreatic ductal adenocarcinoma (PDAC) progression is driven by a poorly understood continuum of plastic malignant cell states between the “classical” (GATA6⁺) and “basal-like” (KRT17⁺) subtypes. Here, we integrate scRNA−seq with quantitative proteomics from laser-capture microdissected patient tissue and targeted mechanistic perturbations to establish a framework that simplifies this continuum and defines malignant programs linked to tumor progression, metastasis, and therapy resistance. We identify a transcriptionally and proteomically distinct KRT17⁺/GATA6⁺ hybrid cell state. Spatial analyses show that hybrid cells are enriched among de-differentiating populations, concentrate at the invasive front of primary tumors, and are significantly overrepresented in lethal liver and lung metastases, indicating that this plastic phenotype is selected during the metastatic cascade. Proteomic deconstruction reveals that the hybrid state is governed by a MYC-driven oncogenic program coupled to a metabolic shift toward oxidative phosphorylation. By individually reducing KRT17 and GATA6 expression, we establish a direct KRT17→c-MYC regulatory axis that promotes broad resistance to standard therapies while creating a specific, targetable vulnerability to MYC inhibition. Together, these findings identify the KRT17⁺/GATA6⁺ hybrid phenotype as a key node of PDAC aggressiveness and therapeutic resistance and support the use of KRT17/GATA6 as biomarkers to stratify patients for clinical trials of MYC inhibitors.
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BibTeX
@misc{delgado2026krt17gata6,
title = {{A KRT17/GATA6 hybrid state marks unique vulnerability to MYC in pancreatic cancer}},
author = {Lyanne Delgado and Andrew Resnick and Jonathan Ogata and Jorge Villar-Samaniego and Qian Lin and Michael Horowitz and Thomas Beggs and Tristan Kwai and Anastasia Terbaci and Kayla Schwartz and Jeremy Loffredo and Katlin Wilson and Nicholas W. Bateman and Kelly A. Conrads and Jacky D. Lin and Anika Porwal and Fjord Deda and Bo Chen and Sruthi Babu and Natalia Marchenko and Emanuel F. Petricoin III and Thomas P. Conrads and Scott Powers and Luisa Escobar-Hoyos and Kenneth Shroyer},
howpublished = {Research Square},
year = {2026},
month = nov,
doi = {10.21203/rs.3.rs-11519779/v1},
url = {https://doi.org/10.21203/rs.3.rs-11519779/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - A KRT17/GATA6 hybrid state marks unique vulnerability to MYC in pancreatic cancer
AU - Lyanne Delgado
AU - Andrew Resnick
AU - Jonathan Ogata
AU - Jorge Villar-Samaniego
AU - Qian Lin
AU - Michael Horowitz
AU - Thomas Beggs
AU - Tristan Kwai
AU - Anastasia Terbaci
AU - Kayla Schwartz
AU - Jeremy Loffredo
AU - Katlin Wilson
AU - Nicholas W. Bateman
AU - Kelly A. Conrads
AU - Jacky D. Lin
AU - Anika Porwal
AU - Fjord Deda
AU - Bo Chen
AU - Sruthi Babu
AU - Natalia Marchenko
AU - Emanuel F. Petricoin III
AU - Thomas P. Conrads
AU - Scott Powers
AU - Luisa Escobar-Hoyos
AU - Kenneth Shroyer
PY - 2026
DA - 2026/11/01
PB - Research Square
DO - 10.21203/rs.3.rs-11519779/v1
UR - https://doi.org/10.21203/rs.3.rs-11519779/v1
AB - Pancreatic ductal adenocarcinoma (PDAC) progression is driven by a poorly understood continuum of plastic malignant cell states between the “classical” (GATA6⁺) and “basal-like” (KRT17⁺) subtypes. Here, we integrate scRNA−seq with quantitative proteomics from laser-capture microdissected patient tissue and targeted mechanistic perturbations to establish a framework that simplifies this continuum and defines malignant programs linked to tumor progression, metastasis, and therapy resistance. We identify a transcriptionally and proteomically distinct KRT17⁺/GATA6⁺ hybrid cell state. Spatial analyses show that hybrid cells are enriched among de-differentiating populations, concentrate at the invasive front of primary tumors, and are significantly overrepresented in lethal liver and lung metastases, indicating that this plastic phenotype is selected during the metastatic cascade. Proteomic deconstruction reveals that the hybrid state is governed by a MYC-driven oncogenic program coupled to a metabolic shift toward oxidative phosphorylation. By individually reducing KRT17 and GATA6 expression, we establish a direct KRT17→c-MYC regulatory axis that promotes broad resistance to standard therapies while creating a specific, targetable vulnerability to MYC inhibition. Together, these findings identify the KRT17⁺/GATA6⁺ hybrid phenotype as a key node of PDAC aggressiveness and therapeutic resistance and support the use of KRT17/GATA6 as biomarkers to stratify patients for clinical trials of MYC inhibitors.
SN - 2693-5015
ER -