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Research

How does metabolism drive cellular decisions?
We aim to understand fundamental questions on adipose biology that are still unanswered: how do metabolites modulate adipogenesis? How can metabolism be leveraged to induce healthy adipose expansion that allows for excess nutrient storage, preventing insulin resistance under a stress of a high fat diet? To begin to understand how metabolites drive adipogenesis, we defined the metabolome associated with early adipocyte differentiation. From this broad analysis we found that branched-chain amino acid (BCAA) catabolism is upregulated early in the differentiation process, and this regulation is not dependent on transcriptional activity of a key adipogenic regulator, transcription factor PPARĪ³. Rather, a mitochondrial sirtuin, SIRT4 promotes BCAA catabolism to induce a nuclear transcriptional program that drives adipogenesis (Zaganjor et al., 2021).

Our new projects of interest are to:

  1. Examine how mitochondria communicate with the nucleus to promote adipogenesis.
  2. Define new mechanisms by which mitochondria activate early adipogenesis using CRISPR screening.
  3. Evaluate the impact of altering mitochondrial metabolism on non-cell autonomous processes using in vivo transgenic and knockout mouse models.

Mitochondrial function in cancer
Metabolic rewiring that supports tumor initiation, progression, metastasis, resistance to chemotherapy, and even immune evasion has been at the center of cancer biology research. Along these lines, we identified critical mitochondrial signaling events that promote cancer growth and metastasis. We found that a sirtuin, SIRT3, a global regulator of mitochondrial metabolism, is down-regulated in basal-like breast cancers, causing these cancers to rewire glutamine metabolism for nucleotide synthesis, driving proliferation (Gonzalez Herrera*, Zaganjor*, et al. 2018). Moreover, we discovered that SIRT3 regulation of reactive oxygen species blocks breast cancer metastasis through Src signaling (Lee*, van de Ven*, Zaganjor*, et al. 2018).

Our new projects aim to:

  1. Elucidate the direct mechanism by which SIRT3 promotes nucleotide synthesis.
  2. Develop screening tools to identify the mechanisms by which loss of SIRT3 promotes migration and metastasis.
  3. Evaluate new strategies to target low-SIRT3 cancer cell proliferation and migration.