Targeting Transglutaminase 2 in cancer cachexia

PROJECT SUMMARY
Cachexia has a devastating impact on survival and quality of life of many cancer patients and remains an unmet
medical need. Pancreatic cancer patients present with the highest incidence of cachexia (~90%), and
approximately one-third of these patients lose more than 10% of their pre-illness weight, leading to general
muscle weakness, impairment of normal activities, and eventually death through respiratory failure. A deeper
understanding of the underlying mechanisms that lead to the complex metabolic defects of cachexia, coupled
with effective treatment options, would improve management of muscle wasting in cancer patients.
We have recently reported that ectopic expression of the transcription factor Twist1 in muscle progenitor
cells is sufficient to cause severe muscle atrophy akin to muscle cachexia. Using several genetic mouse models
of pancreatic ductal adenocarcinoma (PDAC), we detected high Twist1 expression in muscle undergoing cancer
cachexia. Of particular importance, inactivating muscle Twist1, either genetically or pharmacological, was
sufficient to reverse muscle cachexia and improve survival in several genetic mouse models of cancer cachexia,
implicating Twist1 as a possible target for attenuating muscle cachexia in cancer patients.
Quite serendipitously, we found that muscle Twist1 was highly crosslinked during cancer cachexia. We
obtained strong evidence that this process was mediated by the crosslinking enzyme Transglutaminase 2
(TGM2). Treatment of cells with a specific TGM2 inhibitor completely suppressed Twist1-induced expression of
MuRF1 and Atrogin1, two ubiquitin ligases that drive muscle protein degradation during muscle cachexia. Other
preliminary data showed that expression of Twist1 in vivo promotes muscle TGM2 expression. More crucially,
we detected a marked increase in both muscle Twist1 and TGM2 expression in cachectic cancer patients as
compared to healthy individuals, attesting to the clinical relevance of our findings.
Based on these intriguing findings, we hypothesize that TGM2 might function in partnership with Twist1
to orchestrate a feed-forward network that initiates and sustains muscle cachexia during cancer progression. We
also hypothesize that developing combinatorial therapeutic strategies targeting both TGM2 and Twist1 could
mitigate potential drug toxicity by lowering the dose needed for each medicine and combat the development of
resistance. These overarching hypotheses will be tested in our research proposal.
Specific Aim 1: Investigate the relationship between TGM2 and Twist1 during muscle cachexia
Specific Aim 2: Explore the role of the TGM2-Twist1 axis in muscle cachexia using genetic approaches
Specific Aim 3: Test the therapeutic value of targeting both TGM2 and Twist1 in muscle cachexia
We believe that our innovative proposal to exploit this novel TGM2/Twist1 axis in muscle cachexia will culminate
in a paradigm shift in our understanding and therapeutic treatment of this lethal wasting syndrome.

Grant Number: 7R01CA251405-06
NIH Institute/Center: NIH
Principal Investigator: Azeddine Atfi