Carcinoma progression depends on the interactions of epithelial tumor cells with their surrounding stroma. Fibroblasts represent a principal component of this stroma, which modulates tumor cell behavior through diverse mechanisms, including the synthesis of growth and angiogenic factors, cytokines, extracellular matrix components and proteases. Indeed, many solid tumors exhibit striking histological evidence of fibroblast proliferation and activation, termed desmoplasia. Although desmoplasia in human cancers tightly correlates with poor prognosis, the molecular mechanisms that generate and maintain this desmoplastic response remain unknown. In preliminary studies, we have uncovered that autophagy in stromal fibroblasts is crucial for promoting both desmoplasia and tumor progression. Autophagy is a tightly regulated lysosomal degradation process that promotes tumor cell survival and metabolic adaptation. There is great interest in targeting autophagy against cancer due to its well-established effects on tumor cell survival; however, the potential pro- tumorigenic functions of autophagy in the host stroma remain unknown. We hypothesize that autophagy in stromal fibroblasts is critical to initiate and maintain a desmoplastic fibrotic response and to facilitate tumor progression. Using powerful immune-competent mammary cancer models and tools uniquely developed in our laboratory, we will rigorously scrutinize the functions of stromal fibroblast autophagy during cancer progression in vivo.
In Aim 1, we will determine how autophagy in stromal fibroblasts modulates tissue stiffness and ECM remodeling.
In Aim 2, we will dissect how autophagy-dependent secretion by stromal fibroblasts promotes carcinoma progression and influences the tumor microenvironment.
In Aim 3, we will corroborate the effects of stromal fibroblast autophagy in mammary cancer progression and metastasis using autochthonous tumor models. These studies will provide unique conceptual insight into whether and how the autophagy pathway in host fibroblasts can be modulated to abolish the stromal response required for cancer progression.
The tumor microenvironment represents an attractive therapeutic target in cancer. To manifest this concept clinically, we must identify the cellular pathways in host stromal cells that can be exploited to ?short circuit? tumor progression. Our studies dissect whether a fundamental catabolic pathway called autophagy can be targeted in host fibroblasts to abolish the stromal response necessary for cancer cells to expand, survive and invade in vivo.
| Monkkonen, Teresa; Debnath, Jayanta (2018) Inflammatory signaling cascades and autophagy in cancer. Autophagy 14:190-198 |
| Cadwell, Ken; Debnath, Jayanta (2018) Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins. J Cell Biol 217:813-822 |
