Biology subjects

Schwalbe, M.

Publications and source records attributed to Schwalbe, M..

2 recordsLinked to original sources

bioRxiv2020

Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggressive Murine Hepatoblastomas

Background and AimsHepatoblastoma (HB), the most common pediatric liver cancer, often bears {beta}-catenin mutations and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing {beta}-catenin mutants and the constitutively active Hippo effector YAPS127A. Some HBs and other cancers also express mutants of NFE2L2/NRF2 (NFE2L2), a transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis. MethodsWe evaluated NFE2L2s role in HB pathogenesis by co-expressing all combinations of mutant {beta}-catenin, YAPS127A and the patient-derived NFE2L2 mutants L30P and R34P in murine livers. We evaluated growth, biochemical and metabolic profiles and transcriptomes of the ensuing tumors. ResultsIn association with {beta}-catenin+YAPS127A, L30P and R34P markedly accelerated HB growth and generated widespread cyst formation and necrosis, which are otherwise uncommon features. Surprisingly, any two members of the mutant {beta}-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus directly establishing NFE2L2s oncogenicity. Each tumor group displayed distinct features but shared 22 similarly deregulated transcripts, 10 of which perfectly correlated with survival in human HBs and 17 of which correlated with survival in multiple adult cancers. One highly up-regulated transcript encoded serpin E1, a serine protease inhibitor that regulates fibrinolysis, growth and extracellular matrix. The combination of mutant {beta}-catenin, YAPS127A and Serpin E1, while not accelerating cystogenic tumor growth, did promote the wide-spread necrosis associated with mutant {beta}-catenin-YAPS127A-L30P/R34P tumors. ConclusionsOur findings establish the direct oncogenicity of NFE2L2 mutants and key transcripts, including serpin E1, that drive specific HB features.

cancer biology↗

bioRxiv2020

Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. However, capitalizing on this therapeutically has been only moderately successful due to the relatively small magnitude of these differences and because cancers may re-program their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bi-functional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate dodecanedioic acid (DDDA), a toxic C12 metabolite that causes hepatocyte necrosis and acute liver failure. In a murine model of pediatric hepatoblastoma (HB), down-regulation of Ehhadh also occurs in combination with a more general suppression of mitochondrial {beta}- and peroxisomal {omega}-fatty acid oxidation (FAO) pathways. HB-bearing mice provided with C12 and/or DDDA-supplemented diets survived significantly longer than those on standard diets. The tumors also developed massive necrosis in response to short-term DDDA supplementation. Reduced Ehhadh was noted in murine hepatocellular carcinomas (HCCs) and in substantial subsets of human cancers, including HCCs. Acquired DDDA resistance was not associated with Ehhadh re-expression but was associated with 129 transcript differences ~90% of which were down-regulated in DDDA-resistant tumors and ~two-thirds of which correlated with survival in several human cancers. These transcripts often encoded components of the extracellular matrix suggesting that DDDA resistance arises from its reduced intracellular transport. Our results demonstrate the feasibility of a metabolic intervention that is non-toxic, inexpensive and likely compatible with traditional therapies. C12 and/or DDDA-containing diets could potentially be used to supplement other treatments or as alternative therapeutic choices.

cancer biology↗