Integrated G Protein Circuitry for Cancer Cell Signaling Autonomy

SUMMARY/ABSTRACT The Problem: Cancer cells often reside in environments deprived of growth factors and nutrients. Yet they thrive by rewiring their signaling through autocrine and paracrine “secrete-and-sense” circuits, enabling self- sustaining growth. This phenomenon, known as growth signaling autonomy, is one of the earliest recognized hallmarks of cancer and central to cancer stemness, tumor progression, and treatment resistance. However, the core molecular mechanisms driving these circuits remain poorly defined, limiting therapeutic progress. Central premise: Our data identify GIV (Gα-interacting vesicle-associated protein) as a master regulator of cancer cell signaling autonomy. GIV is a multimodular scaffold protein that integrates signaling across monomeric and heterotrimeric G proteins—elements typically studied in isolation—into a coherent, feed-forward signaling circuit that sustains EGF/EGFR-dependent growth. Endogenously expressed in many breast cancers, particularly triple-negative breast cancers (TNBCs), GIV enables cells to sustain tumor progression under nutrient- and growth factor-limiting conditions. In contrast, ER+ BCs, which often lack endogenous GIV, acquire it via intercellular transfer from stromal neighbors, highlighting a novel mode of proteomic exchange. We hypothesize that GIV promotes cancer stem cell-like states, tumor growth, and drug resistance under nutrient- and growth factor-limited conditions. GIV-dependent cancer cell signaling autonomy may also extend to neighboring GIV-deficient cancer cells via paracrine signaling, enhancing cooperative growth among heterogeneous cancer cell populations. Our team—experts in breast cancer biology, GIV signaling, and in the use of both animal and non-animal models (patient-derived organoids and tissue microarrays) alongside synthetic biology tools (cells with engineered circuits) and quantitative live-cell imaging—is uniquely positioned to test this model through integrated experimental and computational approaches. Our aims are to discover how GIV’s modular domains orchestrate key states of cancer cells driving tumor progression in the setting of: (1) intrinsic autonomy in GIV-expressing TNBCs or (2) intercellular transfer- dependent acquired autonomy in ER+BCs; and 3) establish the cooperative dynamics by which GIV-expressing autonomous cells support non-autonomous GIV-deficient neighbors in heterogeneous tumors. We leverage human organoids and tissue microarrays to preserve translational potential and ensure clinical relevance. Impact: This work will redefine cancer signaling by identifying the first mechanistic framework of secrete- and-sense growth factor autonomy within the EGF/EGFR pathway. It will also chart how a single intracellular hub (GIV) coordinates autocrine and paracrine signaling across diverse cell populations to drive tumor progression. By mechanistically linking cancer growth signaling autonomy to stemness, plasticity, tumor heterogeneity and therapeutic resistance, our findings will uncover new intervention points and provide a transformative conceptual advance in targeting signaling rewiring in breast cancer and beyond. Project Number: 1R01CA305983-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Pradipta Ghosh (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $637,509 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CDB-E (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11387989