Tumor loss-of-function mutations in STK11/LKB1 induce cachexia
Puneeth Iyengar, … , John D. Minna, Rodney E. Infante
Puneeth Iyengar, … , John D. Minna, Rodney E. Infante
Published April 24, 2023
Citation Information: JCI Insight. 2023;8(8):e165419. https://doi.org/10.1172/jci.insight.165419.
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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 1

Human NSCLC cachexia screen.

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Human NSCLC cachexia screen. (A) Schema of CC screen. (B–H) Identificati...
(A) Schema of CC screen. (B–H) Identification of human NSCLC lines with and without CC potential. Chow-fed NOD/SCID mice (11- to 12-week-old male mice, n = 6 per cohort) were injected s.c. into the right flank with human NSCLC cells for each of the 54 lines. Measurements of relative terminal fat (B and D) and tumor-free lean (B and E) mass, tumor-free terminal body weight loss (C), average daily food intake (F), terminal tumor volume (G), and tumor growth time to 0.5 cm3 (H) were obtained as described in Methods. CC lines (red circles) were defined if tumor growth occurred within 30 days, relative fat mass loss was >35%, and relative lean mass loss was >5%. Non-CC lines (black circles) were defined if tumor growth occurred within 30 days, relative fat mass loss was <5%, and relative lean mass loss was <5%. Data are shown as mean ± SEM. ****P < 0.0001 was calculated from 2-tailed unpaired t test for significant differences in mean value of the indicated parameter between CC and non-CC groups. CC, cancer cachexia.