Camolotto, S. A. | bioRxiv Science

bioRxiv2020

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. NKX2-1 is required for optimal tumor initiation, but dispensable for growth of established tumors, in BRAFV600E driven disease. NKX2-1-deficient, BRAFV600E driven tumors resemble human IMA and exhibit a distinct response to BRAF/MEK inhibitors. Whereas BRAF/MEK inhibitors drive NKX2-1-positive tumor cells into quiescence, NKX2-1-negative cells fail to exit the cell cycle after the same therapy. BRAF/MEK inhibitors also induce cell identity switching in NKX2-1-negative lung tumors within the gastric lineage, which is driven in part by WNT signaling and FoxA1/2. These data elucidate a complex, reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of lung adenocarcinoma identity that is likely to impact lineage-specific therapeutic strategies.

cancer biology↗

bioRxiv2019

Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: Classical and Basal-like. The Classical subtype is characterized by a more favorable prognosis and better response to chemotherapy than the Basal-like subtype. The Classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor HNF4. Using in vitro and in vivo PDAC models, we show that HNF4 restrains tumor growth and drives tumor cells toward an epithelial identity. Gene expression analysis from murine models and human tumors shows that HNF4 activates expression of genes associated with the Classical subtype. Although HNF4 loss is not sufficient for complete conversion to the Basal-like subtype gene expression profile, HNF4 directly represses SIX4 and SIX1, mesodermal lineage specifiers expressed in the Basal-like subtype. Finally, HNF4-negative PDAC cells rely on expression of SIX4 and SIX1 for proliferation in vitro and in vivo. Overall, our data show that HNF4 regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the Classical gene expression program and repression of SIX4 and SIX1, which may represent novel dependencies of the Basal-like subtype.

cancer biology↗