Despite breakthroughs that have improved the five-year survival of many cancer patients, the long-term prognosis for many patients remains unchanged. My group has been studying the role of the extracellular matrix (ECM) and tissue tension in malignant transformation and progression. Our findings argue that malignancy is fostered by loss of tensional homeostasis induced by genetic modifications and a stiffened ECM that synergistically stimulate actomyosins to alter the cytoskeleton, cell signaling and gene expression.
This research aims to identify conserved molecular mechanisms whereby tension promotes malignancy to identify predictive biomarkers for risk stratification and to develop drug targets for chemoprevention and anti-tumor therapies. Our pilot data showed a stiff ECM induces mitochondrial stress and metabolic reprogramming that promote malignancy and tumor aggression in culture and in vivo. Studies revealed inflammation stiffens the ECM to metabolically reprogram the myeloid cells towards a pro-tumor phenotype that represses anti-tumor immunity. We determined that the ECM in chronically inflamed tissues with elevated risk to malignancy is stiffer and exhibits evidence of mitochondrial stress. Thus, we predict that tissue tension induces mitochondrial stress and compromises anti-tumor immunity to enhance tumor cell growth, survival and invasion and induce genetic perturbations that promote malignancy and tumor aggression and foster metastasis. We have 2D and 3D culture and mouse models with which we can measure, manipulate and modify tissue tension in breast, pancreas and glioblastoma to test these predictions. We will expand these approaches with technical innovations that improve analysis and monitoring of tension-dependent malignancy in vivo and our collaborators will assist with the technical execution and clinical interpretation of the work. We have incorporated molecular and drug screens to identify candidate regulators and inhibitory compounds to develop anti-tumor and chemoprevention treatments.
Despite encouraging breakthroughs that have improved the five-year survival of cancer patients, the long-term prognosis for those with metastatic disease remains dismal. Patient mortality is due primarily to metastatic disease that is resistant to treatment and evades anti-tumor immunity. In this proposal, we seek to identify conserved mechanical reinforcement circuits that drive malignant transformation and progression focusing on inflammation and mitochondrial stress. Completion of the program should provide new insight into how inflammation and the extracellular matrix drive malignancy and foster the evolution of aggressive cancers, clarify how cancers circumvent critical bottlenecks they encounter during tumor progression and identify biomarkers to risk stratify patients and therapies to treat refractory tumors and for chemoprevention.
