Assistant Professor of Biochemistry
Obesity, Diabetes, Cancer, Signaling, Stem Cells, Primary Cilium, Adipose Tissue
The prevalence of obesity has reached pandemic levels, with more than 70% of US adults (and 50% globally) being overweight or obese. We want to understand how obesity-induced changes to fat tissue (white adipose tissue) lead to comorbidities such as cancer and diabetes. In response to excess calories, white adipose tissue has to expand, and this requires the coordinated enlargement of existing fat cells as well as the generation of additional fat cells. Our lab explores the signaling network that enables this coordinated tissue expansion, and how changes to this signaling network result in disease.
Adipose tissue becomes dysfunctional when excess calories exceed the capacity of fat stem cells to generate enough new fat cells, resulting in over-enlargement of existing fat cells and consequently tissue fibrosis, inflammation, and insulin insensitivity. We want to understand what physiological signals activate fat stem cells, how these signals trigger the differentiation of fat stem cells, and why not enough fat stem cells are activated in disease.
We discovered that fat stem cells (like most stem cells) have an antenna-like cellular protrusion called a primary cilium. Cilia are ancient, highly conserved cellular organelles; mutations that compromise the structure and function of the primary cilium cause broad, multisystemic human genetic disorders called ciliopathies. Noted clinical characteristics of ciliopathies include morbid obesity and type 2 diabetes. Strikingly, loss of cilia on fat stem cells prevents their differentiation and the proper expansion of white adipose tissue. We want to identify what receptors localize to the primary cilium of fat stem cells, what physiological signals they sense, and how they regulate the activation and differentiation of fat stem cells. By focusing on signaling pathways that are mediated by the primary cilium, we can (a) leverage advances in human genetics associated with ciliopathies to drive new hypotheses, (b) exploit the specific localization of ciliary receptors to mechanistically interrogate these signaling pathways, and (c) begin to understand how the primary cilium integrates signals for binary cell fate decisions.
Another major interest in my lab is to study the molecular mechanism underlying obesity-accelerated cancer. Obesity increases the incidence of 13 types of cancer. Interestingly, these diverse cancers are all associated with expanded white adipose tissues or sites of steatosis. We want to understand the localized, reciprocal signaling network between cancer cells and the cells in white adipose tissue. We are particularly interested how signals secreted by breast cancer cells change the composition and function of the surrounding white adipose tissue, and how signals secreted by obese white adipose tissue promote breast cancer growth. We are using a powerful combination of ex vivo functional assays and mouse models of breast cancer as well as mass spectrometry and microscopy to identify novel factors that accelerate breast cancer growth. By focusing on intercellular signaling networks connecting cancer cells and white adipose tissue, we can uncover novel targetable modulators of tumorigenesis in general and obesity-accelerated breast cancer in particular.
References (Selected Publications)
- Garritson JD, Zhang J, Achenbach A, Ferhat M, Eich E, Stubben CJ, Martinez PL, Ibele AR, Hilgendorf KI, Boudina S. BMPER is a marker of adipose progenitors and adipocytes and a positive modulator of adipogenesis. Commun Biol. 2023 Jun 13;6(1):638. doi: 10.1038/s42003-023-05011-w. PubMed PMID: 37311809; PubMed Central PMCID: PMC10264349.
- Scamfer SR, Lee MD, Hilgendorf KI. Ciliary control of adipocyte progenitor cell fate regulates energy storage. Front Cell Dev Biol. 2022;10:1083372. doi: 10.3389/fcell.2022.1083372. eCollection 2022. Review. PubMed PMID: 36561368; PubMed Central PMCID: PMC9763467.
- Palla AR, Hilgendorf KI, Yang AV, Kerr JP, Hinken AC, Demeter J, Kraft P, Mooney NA, Yucel N, Burns DM, Wang YX, Jackson PK, Blau HM. Primary cilia on muscle stem cells are critical to maintain regenerative capacity and are lost during aging. Nat Commun. 2022 Mar 17;13(1):1439. doi: 10.1038/s41467-022-29150-6. PubMed PMID: 35301320; PubMed Central PMCID: PMC8931095.
- Hilgendorf KI. Primary Cilia Are Critical Regulators of White Adipose Tissue Expansion. Front Physiol. 2021;12:769367. doi: 10.3389/fphys.2021.769367. eCollection 2021. Review. PubMed PMID: 34759842; PubMed Central PMCID: PMC8573240.
- Hilgendorf KI, Johnson CT, Mezger A, Rice SL, Norris AM, Demeter J, Greenleaf WJ, Reiter JF, Kopinke D, Jackson PK. Omega-3 Fatty Acids Activate Ciliary FFAR4 to Control Adipogenesis. Cell. 2019 Nov 27;179(6):1289-1305.e21. doi: 10.1016/j.cell.2019.11.005. Epub 2019 Nov 21. PubMed PMID: 31761534; PubMed Central PMCID: PMC7332222.
- Hilgendorf KI, Johnson CT, Jackson PK. The primary cilium as a cellular receiver: organizing ciliary GPCR signaling. Curr Opin Cell Biol. 2016 Apr;39:84-92. doi: 10.1016/j.ceb.2016.02.008. Epub 2016 Feb 27. Review. PubMed PMID: 26926036; PubMed Central PMCID: PMC4828300.