Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma known for rapid metastasis and recurrence following treatment. The standard of care (etoposide + cis-platinum and radiation) has hardly changed in over 30 years, with dismal outcomes for patients. There is a pressing need, therefore, for new therapies to treat this deadly disease. Although previously thought of as a homogeneous disease comprised of “small round blue cells,” recent studies have identified numerous subtypes of SCLC that support tumor growth, treatment evasion, and metastasis. Recent work from our lab identified four distinct SCLC subtypes, three of which have been described previously and a fourth which is novel and broadly insensitive to several classes of therapeutic agents, pointing to a possible role in treatment resistance. 

To investigate SCLC tumor growth dynamics and identify factors that can modulate tumor composition, we constructed a population dynamics model incorporating cell-cell interactions. The model features three neuroendocrine (NE) subtypes and one non-NE subtype that provides trophic support to NE cells via secreted factors that enhance cell division and inhibit death. Cells can reversibly transition between all NE subtypes but only one NE variant can transition into the non-NE state. The three NE subtypes are also assumed to secrete factors that inhibit division of non-NE cells. We fit the model to tumor data from two genetically engineered mouse models (GEMMs) with distinct subtype compositions to identify driving factors that can modulate tumor composition. Our analysis points to transition rates and cell-cell interactions as crucial for defining and maintaining subtype proportions within tumors. We speculate that Myc may be central to phenotypic transition rates and the molecular content of secreted factors, in line with experimental data from GEMMs.