Tumor loss-of-function mutations in STK11/LKB1 induce cachexia
Puneeth Iyengar, Aakash Y. Gandhi, Jorge Granados, Tong Guo, Arun Gupta, Jinhai Yu, Ernesto M. Llano, Faya Zhang, Ang Gao, Asha Kandathil, Dorothy Williams, Boning Gao, Luc Girard, Venkat S. Malladi, John M. Shelton, Bret M. Evers, Raquibul Hannan, Chul Ahn, John D. Minna, Rodney E. Infante
Puneeth Iyengar, Aakash Y. Gandhi, Jorge Granados, Tong Guo, Arun Gupta, Jinhai Yu, Ernesto M. Llano, Faya Zhang, Ang Gao, Asha Kandathil, Dorothy Williams, Boning Gao, Luc Girard, Venkat S. Malladi, John M. Shelton, Bret M. Evers, Raquibul Hannan, Chul Ahn, John D. Minna, Rodney E. Infante
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Research Article Metabolism Oncology

Tumor loss-of-function mutations in STK11/LKB1 induce cachexia

Abstract

Cancer cachexia (CC), a wasting syndrome of muscle and adipose tissue resulting in weight loss, is observed in 50% of patients with solid tumors. Management of CC is limited by the absence of biomarkers and knowledge of molecules that drive its phenotype. To identify such molecules, we injected 54 human non–small cell lung cancer (NSCLC) lines into immunodeficient mice, 17 of which produced an unambiguous phenotype of cachexia or non-cachexia. Whole-exome sequencing revealed that 8 of 10 cachexia lines, but none of the non-cachexia lines, possessed mutations in serine/threonine kinase 11 (STK11/LKB1), a regulator of nutrient sensor AMPK. Silencing of STK11/LKB1 in human NSCLC and murine colorectal carcinoma lines conferred a cachexia phenotype after cell transplantation into immunodeficient (human NSCLC) and immunocompetent (murine colorectal carcinoma) models. This host wasting was associated with an alteration in the immune cell repertoire of the tumor microenvironments that led to increases in local mRNA expression and serum levels of CC-associated cytokines. Mutational analysis of circulating tumor DNA from patients with NSCLC identified 89% concordance between STK11/LKB1 mutations and weight loss at cancer diagnosis. The current data provide evidence that tumor STK11/LKB1 loss of function is a driver of CC, simultaneously serving as a genetic biomarker for this wasting syndrome.

Authors

Puneeth Iyengar, Aakash Y. Gandhi, Jorge Granados, Tong Guo, Arun Gupta, Jinhai Yu, Ernesto M. Llano, Faya Zhang, Ang Gao, Asha Kandathil, Dorothy Williams, Boning Gao, Luc Girard, Venkat S. Malladi, John M. Shelton, Bret M. Evers, Raquibul Hannan, Chul Ahn, John D. Minna, Rodney E. Infante

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Figure 2

Gene variant analysis of human NSCLC cachexia.

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Gene variant analysis of human NSCLC cachexia. (A and B) Tumor gene vari...
(A and B) Tumor gene variant burden. The tumor mutation burden of human NSCLC lines was evaluated by calculating the frequency of total variant genes in each line (A) or total high-impact-variant genes in each line (B). (C) Gene variant analysis. Histogram of gene variant enrichment score (GVES) of all 21,200 profiled genes as described in Methods. (D) Heatmap of gene variants of STK11/LKB1 and selected co-occurring genes common to NSCLC. (E) Identification of non-CC (black outer circle), CC (red outer circle), and other (gray outer circle) lines as defined in the CC screen of 37 NSCLC lines associated with wild-type (white-filled circle) or variant (yellow-filled circle) STK11/LKB1. (F) Immunoblot analysis of tumors derived from the indicated cell line with the indicated antibody as described in Methods. (G) Schematic of STK11/LBK1 variants found in screened CC cell lines mapped to kinase domain. P was calculated based on unpaired 2-tailed t test (A and B), Gaussian distribution fitted to a histogram constructed from all log-odds ratios with Bonferroni adjustment (C), or from multiple logistic regression of STK11/LKB1 status with relative lean mass loss and relative fat mass loss (E).