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

Abstract

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.

TGIF 1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma

“…In light of our present study, this discrepancy could be attributed to the genetic alterations in question, as TGIF1 seems to act mainly through repression of Twist1, whereas mutant p53 likely elicits its malignant effects through very complex mechanisms, often involving multiple genes and signaling pathways. It should be noted that our recent published studies have shown that pancreas‐specific deletion of Twist1 elicited either no effect or complete suppression of PDAC, depending on the genetic background (i.e., p16Ink4A deletion versus Trp53 deletion; Parajuli et al , ). These observations appear to reconcile all previously incongruent data regarding Twist1 in the context of PDAC and further shed important insights into the complex roles of this pro‐malignant transcription factor in PDAC, and perhaps in other human malignancies.…”

“…To generate the expression vector encoding Flag‐Twist1, Twist1 cDNA was obtained by PCR using pBABE‐puro‐mTwist1 as template and cloned into pBICEP‐CMV2‐3xFlag. To generate the p16 Luc reporter, genomic DNA (1,200 bp) upstream of the translation start site was amplified by the Genomic‐GC PCR amplification kit (BD Biosciences) using genomic DNA from HMLE cells as previously described (Parajuli et al , ). All cloned DNA fragments and their corresponding mutants were checked by sequencing.…”

“…Tgif1 global knockout ( Tgif1 −/− ), Tgif1.Loxp / Loxp ( Tgif1 fl / fl ), Twist1.Loxp / Loxp ( Twist1 fl / fl ), p16Ink4A‐Luciferase ( p16 Luc ), Loxp‐Stop‐Loxp‐Kras G12D ( LSL.Kras G12D ), CAG‐Loxp‐Stop‐Loxp‐Luciferase ( LSL‐Luc ), and Pdx1‐Cre were described previously (Parajuli et al , ; Zhang et al , ). Loxp‐Stop‐Loxp‐Trp53 R172H ( LSL‐Trp53 R172H ) mice were obtained from the NCI Mouse Repository.…”

Management of Cancer Cachexia: Attempting to Develop New Pharmacological Agents for New Effective Therapeutic Options

“…In the same study, the GEM model KPC (Kras +/LSL−G12D , Trp53 +/R270H , Pdx1 +/Cre ) was reevaluated. Indeed, KPC is a GEM model of PDA (149) that has been recently considered a reliable model of cachexia by a number of studies [e.g., (11,150,151)]. Nonetheless, Talbert et al demonstrated that changes in size and tissue mass of KPC mice did not correlate with PDA progression, and that patterns of gene expression in their SM did not resemble that of PDA patients (144).…”

Prostate tumor–derived GDF11 accelerates androgen deprivation therapy–induced sarcopenia

“…Previously, we used the ActRIIB-Fc ligand trap to demonstrate that catabolic TGF-β family myokines are necessary for castration-induced sarcopenia in tumor-free mice (16). The myokines that induce sarcopenia are primarily muscle derived, and catabolic signaling is paracrine from muscle stem (satellite) cells to myofibers (37), with only a minor endocrine contribution (38). In tumor-free mice, myostatin, activin A, and activin AB levels are increased in skeletal muscle 2 to 4 weeks after castration, prior to the onset of strength and muscle loss that occurs 6 weeks after castration (16).…”