Metastasis is the greatest challenge that people with cancer face—about 90% of cancer deaths can be attributed to metastatic disease. Metastasis starts when individual cancer cells within the primary tumor evolve and acquire new properties that allow them to spread to other tissues and survive there. The understanding of how cancer cells become metastatic is currently limited because of the difficulties in determining where, when, and how tumor cells interact with other tissues as they spread. With this project, a multidisciplinary team at the University of California, San Francisco, led by Andrei Goga, is applying several cutting-edge approaches to get at the roots of metastasis.
One aim of this project is to increase the understanding of tumor heterogeneity, which will help to untangle how certain tumor cells gain metastatic abilities. The researchers are using single-cell analysis and a multi-omic approach (including genomics, epigenomics, transcriptomics, and proteomics) to study different subsets of tumor cells, including cancer stem cells, from model systems. These models include organoids made from patient tumor samples and transgenic mice. Another aim is to understand the role that tumor―host interactions play in metastasis, including elements in the tumor microenvironment that promote the emergence of metastatic cells, the role of the immune system, and how tumor―nerve interactions in the extracellular matrix are associated with tumor aggression. A third aim is to use models to identify vulnerabilities in metastatic tumor cells and apply those findings to develop new cancer treatments.
Madonna MC, Duer JE, Lee JV, Williams J, Avsaroglu B, Zhu C, Deutsch R, Wang R, Crouch BT, Hirschey MD, Goga A, Ramanujam N. In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer. Cancers (Basel). 2021.
Li PJ, Roose JP, Jablons DM, Kratz JR. Bioinformatic Approaches to Validation and Functional Analysis of 3D Lung Cancer Models. Cancers (Basel). 2021.
Marsh T, Tolani B, Debnath J. The pleiotropic functions of autophagy in metastasis. J Cell Sci. 2021.
Kilinc S, Paisner R, Camarda R, Gupta S, Momcilovic O, Kohnz RA, Avsaroglu B, L’Etoile ND, Perera RM, Nomura DK, Goga A. Oncogene-regulated release of extracellular vesicles. Dev Cell. 2021.
Rudnick JA, Monkkonen T, Mar FA, Barnes JM, Starobinets H, Goldsmith J, Roy S, Bustamante Eguiguren S, Weaver VM, Debnath J. Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis. Genes Dev. 2021.
Gonzalez H, Mei W, Robles I, Hagerling C, Allen BM, Hauge Okholm TL, Nanjaraj A, Verbeek T, Kalavacherla S, van Gogh M, Georgiou S, Daras M, Phillips JJ, Spitzer MH, Roose JP, Werb Z. Cellular architecture of human brain metastases. Cell. 2022.
Solvik TA, Nguyen TA, Tony Lin YH, Marsh T, Huang EJ, Wiita AP, Debnath J, Leidal AM. Secretory autophagy maintains proteostasis upon lysosome inhibition. J Cell Biol. 2022.
Li Z, Ferguson L, Deol KK, Roberts MA, Magtanong L, Hendricks JM, Mousa GA, Kilinc S, Schaefer K, Wells JA, Bassik MC, Goga A, Dixon SJ, Ingolia NT, Olzmann JA. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat Chem Biol. 2022.
Lee JV, Housley F, Yau C, Nakagawa R, Winkler J, Anttila JM, Munne PM, Savelius M, Houlahan KE, Van de Mark D, Hemmati G, Hernandez GA, Zhang Y, Samson S, Baas C, Esserman LJ, van ‘t Veer LJ, Rugo HS, Curtis C, Klefström J, Matloubian M, Goga A. Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer. Nat Commun. 2022.
Spanogiannopoulos P, Kyaw TS, Guthrie BGH, Bradley PH, Lee JV, Melamed J, Malig YNA, Lam KN, Gempis D, Sandy M, Kidder W, Van Blarigan EL, Atreya CE, Venook A, Gerona RR, Goga A, Pollard KS, Turnbaugh PJ. Host and gut bacteria share metabolic pathways for anti-cancer drug metabolism. Nat Microbiol. 2022.
Deng N, Minoche A, Harvey K, Li M, Winkler J, Goga A, Swarbrick A. Deep whole genome sequencing identifies recurrent genomic alterations in commonly used breast cancer cell lines and patient-derived xenograft models. Breast Cancer Res. 2022.
Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023.