Studying How Lineage Plasticity Contributes to Cancer Progression
The molecular networks that specify cellular identity and suppress alternative cell fates are tightly regulated during normal tissue homeostasis. The genetic and epigenetic changes that accumulate during cancer progression can disrupt these networks, often with lethal consequences for cancer patients. In many types of cancer, cell identity dictates not only intrinsic malignant potential, but also response to therapy, even in tumors harboring the same targetable mutations. Although tissue of origin is a major determinant of cancer cell identity, cancer cells can also undergo lineage switching in the course of their natural history and in response to the selective pressure of targeted therapy.
Our overall goal is to determine how the loss of cellular identity and acquisition of alternative differentiation states contributes to cancer progression and alters therapeutic response. Ongoing projects are focused on two major themes:
- Mechanisms of lineage switching in lung and pancreatic cancer. We have identified key transcription factors that control cell identity in lung and pancreatic cancer. For example, NKX2-1 enforces a pulmonary differentiation program in lung adenocarcinoma (Snyder et al., Mol Cell 2013). Loss of NKX2-1, in both mouse models or human tumors, causes a pulmonary to gastric transdifferentiation that is driven by FoxA1/2 (Camolotto et al., eLife 2018). Thus, lung adenocarcinomas can be toggled between two dichotomous identities based on the activity of these lineage specifying transcription factors. In pancreatic cancer, we have found that HNF4α and SIX4 enforce dichotomous identities and regulate clinically relevant molecular subtypes (Camolotto et al. Gut 2021).
In contrast to the discrete and dichotomous identities adopted by many cancer cells, there are some circumstances in which individual cancer cells can simultaneously express multiple identity programs. We have uncovered a novel role for FoxA1/2 in maintaining a dual identity (mixed-lineage) state in NKX2-1-positive lung adenocarcinoma (Orstad et al. Dev Cell 2022). FoxA1/2 are critical drivers of proliferation in this disease and can activate both pulmonary and gastric differentiation programs within the same cell, leading to a hybrid state that is critical for cancer progression.
- Therapeutic implications of lineage switching in cancer. Cell identity can have a profound effect on the way tumors respond to targeted therapy. We have found that NKX2-1 levels dictate the response of lung tumors to targeted inhibition of the RAF/MEK pathway (Zewdu et al. eLife 2021). These experiments also demonstrated a surprising degree of crosstalk between cell identity programs and oncogenic signaling pathways. In particular, the activity of RAF/MEK and WNT oncogenic signaling pathways dictated the specific gastric cell type that NKX2-1-negative lung tumor cells most closely resembled. Current experiments are seeking to determine whether this novel crosstalk can be exploited for therapeutic benefit. Our long term translational goal is to uncover novel therapeutic strategies that target lung and pancreatic tumors based on vulnerabilities associated with both their cell identity and genetic driver mutations.
