Katherine Aird, Ph.D.

The Aird lab has three overarching scientific questions:

Cell cycle regulators are critically important for maintaining homeostasis. How oncogenes and tumor suppressors that disrupt the cell cycle affect cancer metabolism is a major focus of the Aird lab. Currently, our work focuses on 3 main cell cycle regulators: cyclin E1, CDKN2A/p16, and DNA damage cell cycle checkpoints (ATM and ATR).

Cyclin E1: The Aird lab has been instrumental in understanding how the oncogene cyclin E1 modulates metabolism and how that influences therapeutic response in cancer. We recently showed that cyclin E1-driven cells use alpha-ketoglutarate for histone acetylation via de novo carnitine synthesis, and identified a therapeutic window for the use of metabolic inhibitors to chemically induce homologous recombination deficiency and sensitize cyclin E1-driven tumors to DNA damaging agents.

p16/CDKN2A: A major focus of the Aird lab has been to understand how the tumor suppressor p16 affects cancer metabolism. p16 is a negative G1-S phase cell cycle regulator that is upregulated during cellular senescence, and its expression is lost in ~50% of all human cancers. The lab has made major inroads into understanding functions of p16 outside of the cell cycle and was the first to identify a role for p16 loss in nucleotide metabolism. Our recent work has demonstrated that p16 loss increases de novo cholesterol synthesis.

DNA damage cell cycle checkpoints: We have explored metabolic roles of the DNA damage cell cycle checkpoint protein ATM and ATR. We reported that inhibition of ATM induces cancer cell uptake of branched chain amino acids via macropinocytosis to support cancer growth. The lab has also interrogated the other major DNA damage response protein ATR in metabolism, and we found that ATR controls mTORC1 activity through de novo cholesterol synthesis. These studies are significant as both ATM and ATR inhibitors are undergoing clinical development for cancer treatment, and our work indicates that metabolic mechanisms drive sensitivity and resistance to these drugs.

These transformative studies pave the way for development of new therapeutic strategies and/or dietary interventions to exploit metabolic vulnerabilities of cancers with alterations in specific cell cycle regulators.

Cell cycle dysregulation is known to influence the microenvironment. For instance, dysregulation of multiple cell cycle checkpoints — including p53, CDKs, and others — is known to affect the immune compartment. This is also evident in aging and senescence, where slowing or arrest of the cell cycle has important paracrine effects through “Inflammaging” and the senescence-associated secretory phenotype (SASP). Therefore, linking the cell cycle, metabolism, and the microenvironment, although not trivial, is rational. Given the open questions that remain in how cell cycle influences metabolism, and vice versa, it is not surprising that little is understood about how cell cycle-driven metabolic changes affect the microenvironment and the fate of neighboring cells in addition to the organism as a whole. Recently, we made an unexpected discovery that cancer cell CDKN2A/p16 loss alters metabolites within the tumor microenvironment to influence immune cell function and response to immunotherapy. We have also recently focused on metabolites in the senescence-associated secretome that have paracrine effects on non-senescent cancer cells. Ongoing studies are aimed at further characterizing which metabolites are differentially imported and exported from cancer cells during cell cycle dysregulation and how they affect pro-tumorigenic phenotypes.

Our studies demonstrate that metabolism plays a central role in the decision tree for cancer cells to enter or exit the cell cycle and that different metabolites and programs provide an extra layer of regulation as to whether cancer cells will senesce or quiesce. As a postdoctoral fellow at The Wistar Institute, Dr. Aird was the first to demonstrate the reversibility of senescence as a consequence of nucleotide and found that dysregulation of nucleotide metabolism is sufficient to drive senescence. The lab has further pushed this field forward by interrogating metabolic regulation of both senescence and quiescence. We discovered that senescence heterochromatin and its associated transcriptional program in cancer cells is driven by alpha-ketoglutarate-mediated changes in histone methylation. We also found that quiescence, traditionally considered a metabolically inactive cell state, is driven by acetate-mediated acetyl-CoA production. These discoveries provide new fundamental evidence for how metabolism controls cell cycle fates and open up new therapeutic opportunities to target metabolic pathways to influence cell proliferation in cancer. Ongoing studies focus on the mechanisms underlying how different metabolic programs lead to the decision between quiescence or senescence