"Poor prognosis of cancer results from two central progression events, (i) the intravasation of cancer cells into blood vessels which leads to metastasis to distant organs and ultimately lethal tumor overload and (ii) cancer cell survival and adaptation to metabolic stress which causes resistance to anti-cancer therapy and limits life expectancy. Using a novel multiphoton microendoscope device recently developed by myself and collaborators, I here aim to overcome tissue penetration limits and identify important progression events deeply inside tumors. The hard- and software of the microendoscope will be optimized for automated position control and panoramic rotation to sample large tissue volumes and validated for stability and safety. We then will address the locations and mechanisms inside tumors that: (1) enable tumor-cell migration and penetration into blood vessels for distant metastasis and (2) mediate enhanced tumor-cell survival and resistance to experimental radiation- and chemotherapy. This basic inventory will serve to address (3) whether and how the niches for both intravasation and resistance overlap and connected with microenvironmental triggers, including defective blood vessels, signalling pathways of malnutrition and hypoxia, and tissue damage. The strategies include 3D microscopy of live fluorescent multi-color tumors and molecular reporters to record cancer cell migration, proliferation and death in the context with embedding tissue structures and metabolic signals. Once identified and characterized, (4) the niches and signals inducing intravasation and resistance (i.e. integrin adhesion receptors, cytoskeletal regulators, metabolic signalling) will be exploited as targets to enhance experimental radiation and chemotherapy. Preclinical microendoscopy will deliver new insight into cancer progression further contribute impulses to microendoscopy for disease monitoring in patients (“optical biopsy”)."