Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers.
Tumor genetics guides patient selection for many new therapies, and cell culture studies have demonstrated that specific mutations can promote metabolic phenotypes. However, whether tissue context defines cancer dependence on specific metabolic pathways is unknown. Kras activation and Trp53 deletion in the pancreas or the lung result in pancreatic ductal adenocarinoma (PDAC) or non-small cell lung carcinoma (NSCLC), respectively, but despite the same initiating events, these tumors use branched-chain amino acids (BCAAs) differently. NSCLC tumors incorporate free BCAAs into tissue protein and use BCAAs as a nitrogen source, whereas PDAC tumors have decreased BCAA uptake. These differences are reflected in expression levels of BCAA catabolic enzymes in both mice and humans. Loss of Bcat1 and Bcat2, the enzymes responsible for BCAA use, impairs NSCLC tumor formation, but these enzymes are not required for PDAC tumor formation, arguing that tissue of origin is an important determinant of how cancers satisfy their metabolic requirements.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. These authors contributed equally to this work.
Jared R
JR
Mayers
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. These authors contributed equally to this work.
Margaret E
ME
Torrence
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Laura V
LV
Danai
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Thales
T
Papagiannakopoulos
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Shawn M
SM
Davidson
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Matthew R
MR
Bauer
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Allison N
AN
Lau
Center for Computational Biology and Bioinformatics and Department of Systems Biology, Columbia University, New York, NY 10027, USA.
Brian W
BW
Ji
Center for Computational Biology and Bioinformatics and Department of Systems Biology, Columbia University, New York, NY 10027, USA.
Purushottam D
PD
Dixit
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Aaron M
AM
Hosios
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Alexander
A
Muir
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Christopher R
CR
Chin
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA. Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Elizaveta
E
Freinkman
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Tyler
T
Jacks
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Brian M
BM
Wolpin
Center for Computational Biology and Bioinformatics and Department of Systems Biology, Columbia University, New York, NY 10027, USA.
Dennis
D
Vitkup
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA. Dana-Farber Cancer Institute, Boston, MA 02115, USA. mvh@mit.edu.
Matthew G
MG
Vander Heiden
D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000235:genetics; D009154:Mutation; D009584:Nitrogen / Q000378:metabolism; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011257:Pregnancy Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000637:Transaminases / Q000235:genetics
D000597:Amino Acids, Branched-Chain; C117307:KRAS protein, human; D015778:Minor Histocompatibility Antigens; D011257:Pregnancy Proteins; C490590:BCAT1 protein, human; D000637:Transaminases; C424463:BCAT2 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D009584:Nitrogen