癌性恶病质症（CC）是肌肉和脂肪组织浪费导致体重减轻的综合症，在实体瘤患者中观察到50％的发生率。CC的管理受到生物标志物的缺乏和驱动其表型的分子知识的限制。为了识别这些分子，我们将54个非小细胞肺癌（NSCLC）人类癌细胞系注入到免疫缺陷小鼠中，其中17个产生了明显的恶病质或非恶病质表型。全外显子测序发现，10个恶病质系中的8个，但没有非恶病质系，具有丝氨酸/苏氨酸激酶11（STK11 / LKB1）突变，一种调节营养传感器AMPK的调节因子。在人类NSCLC和小鼠结肠癌细胞系中沉默STK11 / LKB1，在免疫缺陷（人类NSCLC）和免疫功能（小鼠结肠癌）模型中，移植细胞后会导致体重下降的现象。此肿瘤浪费与肿瘤微环境的免疫细胞代谢程度的改变有关，从而导致局部mRNA表达和CC相关细胞因子的血清水平上升。对NSCLC患者循环肿瘤DNA的突变分析确定了STK11 / LKB1突变和癌症诊断时体重下降的89％一致性。当前数据提供证据，肿瘤STK11 / LKB1的功能丧失是CC的驱动因素，同时作为该浪费综合征的遗传生物标志物。

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.