Hepatic adaptation to chronic metabolic stress primes tumorigenesis
During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles, but chronic nutrient imbalances can induce hepatocyte death and precipitate metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). Despite prior work identifying stress-induced drivers of hepatocyte death, chronic stress' functional impact on surviving cells remains unclear. Through cross-species longitudinal single-cell multi-omics, we show that ongoing stress drives prognostic developmental and cancer-associated programs in non-transformed hepatocytes while reducing their mature functional identity. Creating integrative computational methods, we identify and then experimentally validate master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. Through geographic regression on human tissue microarray spatial transcriptomics, we uncover spatially structured multicellular communities and signaling interactions shaping stress responses. Our work reveals how cells' early solutions to chronic stress can prime future tumorigenesis and outcomes, unifying diverse modes of cellular dysfunction around core actionable mechanisms.
Authors
- Wolfram Goessling (ORCID: https://orcid.org/0000-0001-9972-1569)
- Kellie E. Kolb (ORCID: https://orcid.org/0000-0001-8840-7363)
- Gerhard Lauer (ORCID: https://orcid.org/0000-0003-0230-2574)
- Brandon M. Lehrich (ORCID: https://orcid.org/0000-0003-1003-5605)
- Jeffrey Patterson-Fortin (ORCID: https://orcid.org/0000-0001-8493-8060)
- Miyeko Mana (ORCID: https://orcid.org/0000-0002-5516-4008)
- Chad Walesky (ORCID: https://orcid.org/0000-0003-3800-3453)
- Brian J. Pepe-Mooney (ORCID: https://orcid.org/0009-0002-7516-423X)
- George Eng (ORCID: https://orcid.org/0000-0003-4960-4705)
- Benjamin E. Mead (ORCID: https://orcid.org/0000-0001-7258-7777)
- Satdarshan P. Monga (ORCID: https://orcid.org/0000-0002-8437-3378)
- V. Deshpande
- Adam J. Rubin (ORCID: https://orcid.org/0000-0003-2236-318X)
- Carolyn L. Winston (ORCID: https://orcid.org/0000-0003-0140-2426)
- Katherine J. Aney
- Marc S. Sherman (ORCID: https://orcid.org/0000-0002-6510-069X)
- Constantine N. Tzouanas (ORCID: https://orcid.org/0000-0002-7536-1156)
- Tyler T. Dao (ORCID: https://orcid.org/0000-0003-1468-3896)
- Michelle L. Ramseier (ORCID: https://orcid.org/0000-0002-9201-7656)
- Sanjay M. Prakadan
- Yuzhou Evelyn Tong (ORCID: https://orcid.org/0000-0003-2652-5828)
- Sahar Nissim (ORCID: https://orcid.org/0000-0002-2303-6415)
- Thomas McMahon-Skates
- Titus Butzlaff
- Junyan Tao (ORCID: https://orcid.org/0000-0003-1010-9221)
- Julia Joung
- Colton Smith (ORCID: https://orcid.org/0000-0001-8427-0056)
- Ethan Chen (ORCID: https://orcid.org/0000-0003-1765-8290)
- Alex K. Shalek
- Fangtao Chi
- Woo-Jeong Jeong
- Feng Zhang
- Jessica E.S. Shay
- Ömer H. Yilmaz
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- McGovern Institute for Brain Research (US)
- University of Pittsburgh (US)
- University of Utah (US)
- Huntsman Cancer Institute (US)
- Beth Israel Deaconess Hospital (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- University of Pittsburgh Medical Center (US)
- Whitehead Institute for Biomedical Research (US)
- Dana-Farber Brigham Cancer Center (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Cell
- Published
- 2025-12-22
- DOI
- https://doi.org/10.1016/j.cell.2025.11.031
- Citations
- 2
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 1.61