Our lab has three major emphases centered on improving outcomes for breast cancer: (1) understanding the biology of tumor-microenvironment interactions during metastasis, particularly the role of resident macrophages in shaping anti-tumor immune responses and facilitating metastatic tumor growth; (2) translating these findings toward clinical benefit, such as our investigator-initiated clinical trials testing a Ron kinase inhibitor in bone-metastatic breast cancer and functional precision oncology trials using patient-derived models to predict treatment responses; and (3) developing innovative models of human breast cancer that accurately reflect metastasis and response to therapy.
We initially discovered that the Macrophage Stimulating Protein (MSP)/RON pathway is sufficient for spontaneous metastasis to multiple organs in a mouse model. We also found that MSP/RON expression can stratify breast cancer patients into groups of high or low risk of relapse due to metastatic disease. We have since elucidated the molecular mechanisms of tumor and host RON signaling that contribute to metastasis in mouse models and human breast cancer. In lung metastasis, RON functions in these cells to suppress the anti-tumor immune response, and inhibition of RON boosts CD8+ cytotoxic T cell activity to block metastatic outgrowth. In bone metastasis, RON additionally functions through a novel mechanism in osteoclasts to remodel bone matrix, facilitating tumor growth. RON inhibitors can complement current therapeutic strategies, such as RANKL inhibition, to protect from osteolysis.
To address the need to model heterogeneous human breast cancers in vivo, our lab led some of the earliest efforts to develop patient-derived xenograft (PDX) models for breast cancer. Our first paper on this subject described a bank of orthotopic patient-derived breast cancer xenografts (PDX) and, more importantly, provided models for spontaneous metastasis of breast cancer to multiple organs as occurs in patients. We also published a comprehensive protocol paper that is used as a standard in the field. This work prompted significant interest in the fields of breast cancer, metastasis, personalized medicine, and drug validation - and we have shipped our models to >100 labs and pharmaceutical companies across the world. Besides the technical advance, our work also provided important conceptual advances, in particular, the discovery that positive engraftment of breast cancers is a prognostic indicator of poor survival; the ability to grow in the mouse parallels the ability to metastasize in the human. We have extended this work and recently described use of PDX and organoids for precision medicine in breast cancer
- Lai S-C, Gundlapalli H, Ekiz HA, Jiang A, Fernandez E, Welm AL (2021) Blocking short-form Ron eliminates breast cancer metastases through accumulation of stem-like CD4+ T cells that subvert immunosuppression. Cancer Discovery (in press).
- Guillen KP*, Fujita M*, Butterfield AJ* … Welm BE**, and Welm AL** (2021) A breast cancer patient-derived xenograft and organoid platform for drug discovery and precision oncology. BioRxiv doi: https://doi.org/10.1101/2021.02.28.433268 *co-first authors; **co-corresponding authors (in revision, Nature Cancer)
- doi: 10.1080/2162402X.2019.1685300. A Pipeline for Identification and Validation of Tumor-Specific Antigens in a Mouse Model of Metastatic Breast Cancer, Oncoimmunology, 9(1):1685300.
- The Importance of Developing Therapies Targeting the Biological Spectrum of Metastatic Disease, Clin Exp Metastasis, 36(4):305-309. doi: 10.1007/s10585-019-09972-3.
- Understanding the Bone in Cancer Metastasis, J Bone Miner Res, 33(12):2099-2113.doi: 10.1002/jbmr.3618.
- mTORC1 Is a Key Mediator of RON-dependent Breast Cancer Metastasis With Therapeutic Potential, NPJ Breast Cancer, 4:36. PMCID: PMC6226524
- Ekiz HA, Lai S-CA, Gundlapalli H, Haroun F, Williams MA, Welm AL (2018): Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth, OncoImmunology, 7(9):e1480286. PMID: 30228950
- Andrade K, Fornetti J, Zhao L, Miller SC, Randall RL, Anderson N, Waltz SE, McHale M, Welm AL (2017) RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis. Sci Transl Med. 9(374). PMID: 28123075
- Bieniasz M, Radhakrishnan P, Faham N, De La O JP, Welm AL (2015) Preclinical Efficacy of Ron Kinase Inhibitors Alone and in Combination with PI3K Inhibitors for Treatment of sfRon-Expressing Breast Cancer Patient-Derived Xenografts. Clin Cancer Res, 21(24):5588-600
- Cunha S, Lin YC, Goossen EA, DeVette CI, Albertella MR, Thomson S, Mulvihill MJ, Welm AL (2014) The RON receptor tyrosine kinase promotes metastasis by triggering MBD4-dependent DNA methylation reprogramming. Cell Rep, 6(1):141-54
- Eyob H, Ekiz HA, Welm AL (2013) RON promotes the metastatic spread of breast carcinomas by subverting antitumor immune responses. Oncoimmunology, 2(9):e25670
- DeRose YS, Gligorich KM, Wang G, Georgelas A, Bowman P, Courdy SJ, Welm AL, Welm BE (2013) Patient-derived models of human breast cancer: protocols for in vitro and in vivo applications in tumor biology and translational medicine. Curr Protoc Pharmacol. Chapter 14:Unit14.23
- Al-Ejeh F, Shi W, Miranda M, Simpson PT, Vargas AC, Song S, Wiegmans AP, Swarbrick A, Welm AL, Brown MP, Chenevix-Trench G, Lakhani SR, Khanna KK (2013) Treatment of Triple-Negative Breast Cancer Using Anti-EGFR Directed Radioimmunotherapy Combined with Radiosensitizing Chemotherapy and PARP Inhibitor. J Nucl Med, 54(6):913-21
- Chaturvedi A, Hoffman LM, Welm AL, Lessnick SL, Beckerle MC (2012) The EWS/FLI Oncogene Drives Changes in Cellular Morphology, Adhesion, and Migration in Ewing Sarcoma. Genes Cancer, 3(2):102-16
- Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, Shin JJ, Harbom KM, Beaty R, Pappou E, Harris J, Yen RW, Ahuja N, Brock MV, Stearns V, Feller-Kopman D, Yarmus LB, Lin YC, Welm AL, Issa JP, Minn I, Matsui W, Jang YY, Sharkis SJ, Baylin SB, Zahnow CA (2012) Transient Low Doses of DNA-Demethylating Agents Exert Durable Antitumor Effects on Hematological and Epithelial Tumor Cells. Cancer Cell, 21(3):430-46
- Smith B, Welm AL, Welm BE (2012) On the shoulders of giants: A historical perspective of unique experimental methods in mammary gland research. Semin Cell Dev Biol, 23(5): 583–590
- Liu X, Zhao L, Derose YS, Lin YC, Bieniasz M, Eyob H, Buys SS, Neumayer L, Welm AL (2011) Short-Form Ron Promotes Spontaneous Breast Cancer Metastasis through Interaction with Phosphoinositide 3-Kinase. Genes Cancer, 2(7):753-62
- DeRose YS, Wang G, Lin YC, Bernard PS, Buys SS, Ebbert MT, Factor R, Matsen C, Milash BA, Nelson E, Neumayer L, Randall RL, Stijleman IJ, Welm BE, Welm AL (2011) Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med, 17(11):1514-20
- Larrieu-Lahargue F, Welm AL, Thomas KR, Li DY (2011) Netrin-4 activates Endothelial Integrin α6β1. Circ Res, 109(7):770-4
- Powers MA, Fay MM, Factor RE, Welm AL, Ullman KS (2011) Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4. Cancer Res, 71(16):5579-87
- Kretschmann KL, Eyob H, Buys SS, Welm AL (2010) The macrophage stimulating protein/Ron pathway as a potential therapeutic target to impede multiple mechanisms involved in breast cancer progression. Curr Drug Targets, 11(9):1157-68
- Kim S, Welm AL, Bishop JM (2010) A dominant mutant allele of the ING4 tumor suppressor found in human cancer cells exacerbates MYC-initiated mouse mammary tumorigenesis. Cancer Res, 70(12):5155-62
- Larrieu-Lahargue F, Welm AL, Thomas KR, Li DY (2010) Netrin-4 induces lymphangiogenesis in vivo. Blood, 115(26):5418-26
- Welm AL (2008) TGFbeta primes breast tumor cells for metastasis. Cell, 133(1):27-8
- Welm BE, Dijkgraaf GJ, Bledau AS, Welm AL, Werb Z (2008) Lentiviral transduction of mammary stem cells for analysis of gene function during development and cancer. Cell Stem Cell, 2(1):90-102
- Welm AL, Sneddon JB, Taylor C, Nuyten DS, van de Vijver MJ, Hasegawa BH, Bishop JM (2007) The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans. Proc Natl Acad Sci U S A, 104(18):7570-5
- Welm AL, Kim S, Welm BE, Bishop JM (2005) MET and MYC cooperate in mammary tumorigenesis. Proc Natl Acad Sci U S A, 102(12):4324-9