Research
What determines the behavior and appearance of different types of cancers?
Several factors may be involved, including the kind of normal cell from which a cancer arises (the “cell of origin”) and the set of specific genes (especially tumor suppressors and proto-oncogenes) that are altered during the conversion of a normal cell to a malignant one. The variations in appearance, behavior and the affected genes often correlate with a specific cell of origin, suggesting that different cell lineages show different responses to various genetic changes. Context is key — not every oncogene is broadly oncogenic.
Patterns of somatic mutations help to distinguish different types of cancer. The main histologic subtypes of lung cancer — lung adenocarcinoma (LUAD), squamous cell carcinoma (SqCC) and small cell lung cancer (SCLC) — are genetically different and thought to arise from different cells of origin. These patterns are particularly unique when contrasting LUAD to SCLC. Whereas LUAD originates from alveolar epithelial cells in the distal lung and is frequently “driven” by signaling through the mitogen activated protein kinase (MAPK) pathway, SCLC occurs in the proximal lung from pulmonary basal and neuroendocrine cells and rarely possesses driver alterations in the MAPK pathway. Instead, loss of the tumor suppressor genes RB1 and TP53 are hallmarks of SCLC.
Some types of cancers, such as LUAD and the prostate adenocarcinomas, can undergo dramatic changes in appearance and behavior and display an altered genetic profile when they develop resistance to targeted therapies. In lung cancers, this “histological transformation” (or HT) can result in the conversion of LUAD into an aggressive type of neuroendocrine cancer indistinguishable from small cell lung cancer (SCLC), which is therapeutically recalcitrant and connotes poor prognosis.
Cancer development within a given niche (i.e. the tumor and tumor microenvironment) is a complex series of events that requires mechanistic interrogation to better understand, and ultimately, control. Using a combination of genetically engineered mouse models (GEMMs), organotypic cultures, high-resolution imaging and single cell approaches, we aim to better understand what the earliest stages of progression "look like" and how certain layers of the innate and adaptive immune system attempt to control cancer initiation, progression and recurrence. We emphasize mechanistic interrogation of complex cancer phenomena, including lineage plasticity, therapeutic resistance and chromosomal instability. Toward these ends, we collaborate broadly with many groups throughout the United States who each bring their specific skills and training histories to unite in common goals to understand, detect and treat cancer with curative intent.
Targetable Transition States in Lung Cancer Development
Different histologic subtypes of lung cancer are thought to originate from distinct cells of origin based on their histologic appearance, anatomic location and patterns of genomic alterations. We’ve developed genetically engineered mouse models of histological transformation between lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) where our goals are to identify targetable features of both residual disease and transition states (i.e., the “plastic intermediate”) that appear prior to the emergence of a permanent shift in lineage commitment. By combining single cell approaches with in vivo perturbations, our goal is to identify features that are required for permitting such profound leaps in plasticity and then build pre-clinical research tools to demonstrate whether we can therapeutically suppress or prevent this phenomenon.
Reconstructing Temporal Lung Cancer Development
One challenge with interpreting data from biological snapshots is exactly just that — these are moments in time. A singular, static view of something that takes time. To better understand how normal neuroendocrine transformation occurs within the lung, we have built large data atlases of temporal transformation from normal cells of origin through late-stage disease, with and without certain perturbations that can accelerate or decelerate the kinetics of transformation. These continuous, multi-modal datasets are thus useful to better characterize tumor niche remodeling over time and understand how layers of the innate and adaptive immune system initially sense and survey burgeoning cancers. By studying the earliest events restricting transformation across a diverse histologic spectrum of lung cancers, our goal is to identify both histological subtype-specific (i.e., LUAD versus SCLC) and generic (i.e., pan-histology) features of airway transformation so that we can better target early stage lung cancers and catch certain types of pre-invasive disease that have notoriously been hard to detect early using existing approaches.
Identifying Lineage Specific Immunomodulatory Secreted Peptides
Most lung cancers arise in secretory cell types, meaning that these cells make specialized biomolecules including lipids, RNAs, proteins, peptides and small molecule metabolites that they package and secrete locally or systemically. For some types of information (i.e., DNA or RNA) we have deeply characterized many individual cell types for their catalog of genes and expressed transcripts. In contrast, such information is less clear for small peptides and their modifications. Moreover, the physiologic context under which these biomolecules may or may not be generated often precludes definitive characterization — the in vivo environment is critical. To address these limitations, we have generated new alleles that permit lineage specific (i.e., DNA recombinase-restricted) and temporal labeling (i.e., administration of exogenous chemicals) of the nascent and secreted proteomes to better characterize what cancers make as they transform and following therapeutic interventions like immunotherapy or targeted therapies. Our goals are to:
- Identify molecules that have a role in suppressing the activity and fidelity of the immune system
- Design neutralizing strategies against select secreted targets, where such approaches can be used in combination with other approved immunotherapies to deepen efficacy