Cachexia is characterized by progressive skeletal muscle and body weight loss and affects up to 80% of cancer patients. This loss of muscle mass contributes to significant muscle weakness and diminished physical function and is associated with reduced tolerance to chemotherapy and increased complications from surgical/radiotherapeutic treatments. Consequently, cachexia decreases both quality of life and survival time in cancer patients and cachexia itself is responsible for up to 30% of all cancer-related deaths. Interestingly muscles from preclinical models of cancer cachexia as well as cachectic human cancer patients show disruptions in sarcomere and myofiber membrane integrity despite the lack of an injury stimulus, and there is speculation that these disruptions may initiate catabolic processes which lead to the muscle atrophy and weakness. Unpublished and preliminary data from our lab has identified that Kyphoscoliosis peptidase (Ky), which is essential to the structural integrity of the sarcomeric Z-disk, and Myocilin (Myoc), which is important to the sarcolemmal dystrophin associated protein complex (DAPC), are highly downregulated at the mRNA and protein level at time points which precede and parallel muscle atrophy and weakness during tumor progression. Moreover, preliminary data show that overexpression of Ky in the muscles of tumor bearing mice inhibits muscle fiber atrophy. These observations support our first hypothesis that the downregulation of Ky and Myoc are causative to the loss of muscle structure leading to muscle wasting and weakness during the progression of cancer cachexia. Unpublished bioinformatics analyses of the -1kb to +1kb proximal promoters of genes significantly downregulated in skeletal muscle of C26 tumor-bearing mice revealed a conserved consensus binding motif for myocyte enhancing factor-2 (MEF2) among the top most commonly shared motifs. Moreover, both the Ky and Myoc gene promoters contain conserved MEF2 binding motifs. This observation, coupled with the findings that MEF2 protein c (MEF2c) is decreased at the mRNA and protein level in tumor bearing mice, supports our second hypothesis that loss of MEF2c transcriptional activity in skeletal muscle of tumor-bearing hosts is causative in the downregulation of Ky and Myoc, and initiates disruptions in muscle fiber integrity and muscle wasting. Thus, our two specific aims are:
Specific Aim 1 : To test the hypothesis that the downregulation of Kyphoscoliosis peptidase (Ky) and Myocilin (Myoc) play causative roles in the cancer-induced loss of muscle fiber integrity and the initiation of muscle wasting.
Specific Aim 2 : To test the hypothesis that loss of MEF2c transcriptional activity is causative in the cancer- induced downregulation of Ky and Myoc and initiates muscle wasting. The results of these studies will provide new insight into transcriptional mechanisms involving protein downregulation which initiate cancer-induced muscle wasting and weakness, opening up new avenues for therapeutic interventions.
Cancer is associated with skeletal muscle atrophy and dysfunction of the contractile apparatus, both of which contribute to muscle weakness and functional impairment in cancer patients. In the proposed experiments we will determine the extent to which a downregulation of specific genes localized to the structural and functional units of skeletal muscle cells, the membrane and the sarcomere, cause cancer-induced muscle atrophy and weakness. We will also study the regulation of these genes during the progression of cancer-induced muscle wasting. Identifying novel therapeutic targets to counter cancer-induced muscle atrophy and weakness could represent a major breakthrough for this debilitating condition.
|Delitto, Daniel; Judge, Sarah M; Delitto, Andrea E et al. (2017) Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia. Oncotarget 8:1177-1189|
|Go, Kristina L; Delitto, Daniel; Judge, Sarah M et al. (2017) Orthotopic Patient-Derived Pancreatic Cancer Xenografts Engraft Into the Pancreatic Parenchyma, Metastasize, and Induce Muscle Wasting to Recapitulate the Human Disease. Pancreas 46:813-819|