Tumor loss-of-function mutations in STK11/LKB1 induce cachexia
Puneeth Iyengar1,2,3, Aakash Y Gandhi1,3, Jorge Granados1
1Center for Human Nutrition.
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.
Insights
Loss of STK11/LKB1 function in tumors drives cancer cachexia (CC), a wasting syndrome. This genetic alteration serves as a biomarker for CC, aiding in diagnosis and management of this condition.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer cachexia (CC) is a wasting syndrome affecting 50% of solid tumor patients, characterized by muscle and adipose tissue loss.
- Current CC management is hindered by a lack of reliable biomarkers and understanding of its underlying molecular drivers.
- Identifying molecules that drive CC phenotype is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To identify molecular drivers of cancer cachexia (CC) by analyzing human non-small cell lung cancer (NSCLC) lines.
- To investigate the role of serine/threonine kinase 11 (STK11/LKB1) in the development of CC.
- To establish STK11/LKB1 mutations as a potential genetic biomarker for CC.
Main Methods:
- Injected 54 human NSCLC lines into immunodeficient mice to observe cachexia phenotypes.
- Performed whole-exome sequencing on cachectic and non-cachectic tumor lines to identify genetic mutations.
- Utilized gene silencing techniques to assess the impact of STK11/LKB1 on CC development in both NSCLC and murine colorectal carcinoma models.
- Analyzed circulating tumor DNA from NSCLC patients to correlate STK11/LKB1 mutations with weight loss.
Main Results:
- Mutations in STK11/LKB1 were found in 8 of 10 cachexia-inducing NSCLC lines, but none of the non-cachexia lines.
- Silencing STK11/LKB1 in cancer cells induced a cachexia phenotype in transplanted models.
- Tumor STK11/LKB1 loss of function altered the tumor microenvironment's immune cell repertoire, increasing CC-associated cytokines.
- An 89% concordance was observed between STK11/LKB1 mutations in circulating tumor DNA and weight loss in NSCLC patients.
Conclusions:
- Tumor loss of function in STK11/LKB1 is a key driver of cancer cachexia.
- STK11/LKB1 mutations can serve as a predictive genetic biomarker for cancer cachexia in patients.
- These findings provide a molecular basis for CC and offer a potential diagnostic tool.
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