Different tumor states (TS) exist within a given tumor with some cancer cells actively dividing, while others differentiate, invade the surrounding tissues, give rise to metastasis, or are in a dormant and therapy-resilient state. The identification of the intrinsic and extrinsic mechanisms that modulate TS diversity is essential for the development of new therapeutic strategies. In this project, we will dissect the mechanisms by which stromal-cancer cell communications influence the gene regulatory networks (GRNs), that defined TS identity in skin cancers. We will take advantage of recent advances in single-cell lineage tracing, single-cell (spatial) multi-omics, microfluidics and bio-informatics to map the spatial distribution of the different TS and their neighboring stromal cells, study how these cellular and molecular (e.g. ligand/receptor) interactions remodel the GRNs and epigenome of cancer cells and thereby regulate their specific TS identity. We will use dynamic models to assess how these interactions evolve during tumor progression, metastasis, and in response to therapy. We will reconstitute or deplete specific stromal-tumor cell interaction(s) or perturb their molecular communications and assess the impact of these perturbations on the GRN controlling TS identity. Finally, we will assess whether pharmacological interventions targeting selected stromal-tumor communications can restrict tumor growth, metastasis or alleviate resistance to therapy.