Hepatic adaptation to chronic metabolic stress primes tumorigenesis

Constantine N Tzouanas; Jessica E S Shay; Marc S Sherman; Adam J Rubin; Benjamin E Mead; Tyler T Dao; Junyan Tao; Brandon M Lehrich; George Eng; Jeffrey Patterson-Fortin; Titus Butzlaff; Miyeko D Mana; Kellie E Kolb; Chad Walesky; Brian J Pepe-Mooney; Colton J Smith; Sanjay M Prakadan; Michelle L Ramseier; Yuzhou Evelyn Tong; Julia Joung; Fangtao Chi; Thomas McMahon-Skates; Carolyn L Winston; Woo-Jeong Jeong; Katherine J Aney; Ethan Chen; Sahar Nissim; Feng Zhang; Vikram Deshpande; Satdarshan P Monga; Georg M Lauer; Wolfram Goessling; Ömer H Yilmaz; Alex K Shalek

doi:10.1016/j.cell.2025.11.031

Hepatic adaptation to chronic metabolic stress primes tumorigenesis

Cell. 2026 Jan 22;189(2):435-460.e28. doi: 10.1016/j.cell.2025.11.031. Epub 2025 Dec 22.

Authors

Constantine N Tzouanas¹, Jessica E S Shay², Marc S Sherman³, Adam J Rubin⁴, Benjamin E Mead⁵, Tyler T Dao⁶, Junyan Tao⁷, Brandon M Lehrich⁸, George Eng⁹, Jeffrey Patterson-Fortin¹⁰, Titus Butzlaff¹¹, Miyeko D Mana¹², Kellie E Kolb⁵, Chad Walesky¹³, Brian J Pepe-Mooney¹⁴, Colton J Smith¹⁵, Sanjay M Prakadan⁵, Michelle L Ramseier¹, Yuzhou Evelyn Tong¹, Julia Joung¹⁶, Fangtao Chi¹⁷, Thomas McMahon-Skates¹³, Carolyn L Winston¹³, Woo-Jeong Jeong¹⁸, Katherine J Aney¹⁹, Ethan Chen²⁰, Sahar Nissim²¹, Feng Zhang²², Vikram Deshpande²³, Satdarshan P Monga²⁴, Georg M Lauer²⁵, Wolfram Goessling²⁶, Ömer H Yilmaz²⁷, Alex K Shalek²⁸

Affiliations

¹ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Division of Gastroenterology, Hepatology & Nutrition, University of Utah, Salt Lake City, UT, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
³ Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁸ Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹¹ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; School of Life Sciences, Arizona State University, Tempe, AZ, USA.
¹³ Division of Gastroenterology, Hepatology & Nutrition, University of Utah, Salt Lake City, UT, USA.
¹⁴ Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Science, MIT, Cambridge, MA, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA, USA; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
¹⁷ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁸ Division of Gastroenterology, Hepatology & Nutrition, University of Utah, Salt Lake City, UT, USA; Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁹ Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA.
²⁰ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA.
²¹ Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²² Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Science, MIT, Cambridge, MA, USA; McGovern Institute for Brain Research, MIT, Cambridge, MA, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA, USA.
²³ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
²⁴ Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁶ Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Gastroenterology, Hepatology & Nutrition, University of Utah, Salt Lake City, UT, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA. Electronic address: wgoessling@mgh.harvard.edu.
²⁷ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Developmental and Regenerative Biology Program, Harvard Medical School, Boston, MA, USA. Electronic address: ohyilmaz@mit.edu.
²⁸ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: shalek@mit.edu.

Abstract

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.

Keywords: chronic stress response; computational methods development; epigenetic priming; genetic perturbation; liver; metabolism; single-cell genomics; tissue memory.

MeSH terms

Adaptation, Physiological*
Animals
Carcinogenesis* / metabolism
Carcinogenesis* / pathology
Cell Proliferation
Hepatocytes* / metabolism
Hepatocytes* / pathology
Humans
Liver Neoplasms* / metabolism
Liver Neoplasms* / pathology
Liver* / metabolism
Liver* / pathology
Male
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease / metabolism
Non-alcoholic Fatty Liver Disease / pathology
Single-Cell Analysis
Stress, Physiological*
Transcriptome

Abstract

MeSH terms

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