Re-programming by a six-factor-secretome in the patient tumor ecosystem during nutrient stress and drug response

Cancer cells need nutrients to grow and proliferate. During nutrient stress in the microenvironment, it is unclear if or how cancer cells can adopt alternative resources to re-wire and survive in patients. We discovered a 6-factor-secretome remarkably sustains a critical cell mass during nutrient stress in a pediatric embryonal brain tumor, atypical teratoid rhabdoid tumor (ATRT). Specific ATRT subtypes emerged as secretome-enriched, matching macrophage-enrichment patterns and were high-relapse-risk subtypes. The secretome alters drug response, protects against cell death, and provides pro-survival niches to rescue drugged cells. Secretome-grown tumor cells rearrange into a web-like architecture-stable during drug exposure, suggesting a mechanism for therapy resistance. Secretome prevents tumor cell death in aggressive tumor models, and in cerebrospinal dissemination, suggesting a role in tumor resistance/relapse. Our results unravel, a previously unexplored role of a specific 6-factor-secretome, providing an alternative fuel to sustain cancer cells during nutrient stress, and implications in relapse subtypes.