Although tumor cell endogenous genetic mutations are major driving forces of tumor progression, recent work has established that cancer growth is also profoundly modulated by tumor cell exogenous interactions with its host. Specifically, cancer outgrowth may be controlled by various immune cell types, which either suppress or promote tumor progression and metastasis, and may be regulated in part by cancer cells directly. This application is dedicated to use new technology to investigate how cancer cells communicate with distant cells in the body, and whether and how this communication affects cancer growth. We will specifically study tumor-derived microvesicles (tMVs) as conveyors of information between tumor cells and immune cells that reside away from the tumor stroma. tMVs carry tumor-derived material (proteins, mRNAs), travel short or long distances in the body while keeping their contents undegraded and undiluted, and may interact with (and by extension control) different host cell types in remote tissues; however, the biological functions of tMVs remain largely unknown. A critical barrier to progress in the field has been our limited ability to understand the impact of tMVs that are produced endogenously in vivo. Indeed, the body of work on tMV-immune cell interactions so far has required the use of in vitro-manipulated tMVs, which may not allow one to fully recapitulate the features of endogenously produced particles. At present, the precise location and identity of immune cells interacting with endogenously produced tMVs is unknown, as is the impact of such interactions on tumor progression. To shift current experimental research approaches to study tMVs directly in vivo, this 2-year project will combine: 1) molecular imaging and 2) new genetic approaches to track endogenously produced tMVs and their targets at different resolutions and scales (organismal, cellular and molecular). Findings from this research should not only validate important new tools to study tumor cell-host cell interactions in many different experimental settings, but also deepen our understanding of tMVs and ultimately open up new avenues for anti-cancer therapy.
Tumor-derived microvesicles (tMVs) are particles which can travel long distances in the body and contain tumor-derived material that can be potentially delivered to distant host cells; however, the biological functions of tMVs produced endogenously in vivo remain largely unknown. Here we will develop and validate novel genetic approaches to track endogenous tMVs at the organismal, cellular, and molecular levels in tumor-bearing mice; these approaches are aimed to uncover how tMVs operate in the body, which host cells they influence, and, eventually, how they modulate tumor progression.
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| Pucci, Ferdinando; Garris, Christopher; Lai, Charles P et al. (2016) SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science 352:242-6 |
| Pfirschke, Christina; Engblom, Camilla; Rickelt, Steffen et al. (2016) Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity 44:343-54 |
| Pucci, Ferdinando; Rickelt, Steffen; Newton, Andita P et al. (2016) PF4 Promotes Platelet Production and Lung Cancer Growth. Cell Rep 17:1764-1772 |
