Twist1 Activation in Muscle Progenitor Cells Causes Muscle Loss Akin to Cancer Cachexia

Publication date: 18 June 2018
Source:Developmental Cell, Volume 45, Issue 6
Author(s): Parash Parajuli, Santosh Kumar, Audrey Loumaye, Purba Singh, Sailaja Eragamreddy, Thien Ly Nguyen, Seval Ozkan, Mohammed S. Razzaque, Céline Prunier, Jean-Paul Thissen, Azeddine Atfi
Cancer cachexia is characterized by extreme skeletal muscle loss that results in high morbidity and mortality. The incidence of cachexia varies among tumor types, being lowest in sarcomas, whereas 90% of pancreatic ductal adenocarcinoma (PDAC) patients experience severe weight loss. How these tumors trigger muscle depletion is still unfolding. Serendipitously, we found that overexpression of Twist1 in mouse muscle progenitor cells, either constitutively during development or inducibly in adult animals, caused severe muscle atrophy with features reminiscent of cachexia. Using several genetic mouse models of PDAC, we detected a marked increase in Twist1 expression in muscle undergoing cachexia. In cancer patients, elevated levels of Twist1 are associated with greater degrees of muscle wasting. Finally, both genetic and pharmacological inactivation of Twist1 in muscle progenitor cells afforded substantial protection against cancer-mediated cachexia, which translated into meaningful survival benefits, implicating Twist1 as a possible target for attenuating muscle cachexia in cancer patients.

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Parajuli et al. show that both genetic and pharmacological inhibition of Twist1 preserves muscle mass and extends lifespan in several mouse models of cancer cachexia, highlighting Twist1 as an attractive therapeutic target for attenuating muscle cachexia and associated morbidity and mortality in advanced cancer patients.


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