Growth Signaling Autonomy in Circulating Tumor Cells Aids Metastatic Seeding

Self-sufficiency (autonomy) in growth signaling, the earliest recognized hallmark of cancer, is fuelled by the tumor cell’s ability to ‘secrete-and-sense’ growth factors; this translates into cell survival and proliferation that is self-sustained by auto-/paracrine secretion. Using breast cancer cells that are either endowed or impaired in growth signaling autonomy, here we reveal how autonomy impacts cancer progression. Autonomy is associated with enhanced molecular programs for stemness, immune evasiveness, proliferation, and epithelial-mesenchymal plasticity (EMP). Autonomy is both necessary and sufficient for anchorage-independent growth factor-restricted proliferation and resistance to anti-cancer drugs and is required for metastatic progression. Transcriptomic and proteomic studies show that autonomy is associated with self-sustained EGFR/ErbB signaling. A gene expression signature is derived (a.k.a., autonomy signature) which revealed that autonomy is induced in circulating tumor cells (CTCs) and particularly CTC clusters, the latter of which carry higher metastatic potential. Autonomy in CTCs tracks therapeutic response and prognosticates outcome. Autonomy is preserved during reversible (but not stable) EMT. These data support a role for growth signaling autonomy in multiple processes essential for the blood-borne dissemination of human breast cancer. WT and GIV-KO MDA-MB231 cells grown in 0% and 10% serum concentration in p10 dishes (Corning) for 16 h prior to harvest, and cell pellets were subsequently processed for RNA extraction using a kit (R2052, Zymo Research) as per manufacturer’s protocol. Isolated RNA has been processed for RNA sequencing in the Illumina NovaSeq 6000 platform.