Biology subjects

Snyder, E. L.

Publications and source records attributed to Snyder, E. L..

6 recordsLinked to original sources

bioRxiv2025

Characterization of the BRAF interactome identifies BRAFV600E<=>TP53 interaction in melanoma

Melanoma is a highly aggressive and frequently metastatic cancer with its incidence reported to be on the rise. Although most oncogenic drivers in melanoma converge on activation of the RAS>RAF>MEK>ERK MAPK signaling pathway, not all MAPK-activating mutations are recurrently observed in this disease, suggesting a unique functional role for BRAFV600E, which is present in [~]50% of all melanoma cases. However, the prevalence of BRAFV600E alterations over other known MAPK-promoting oncoproteins raises questions regarding whether BRAFV600E possesses additional functions outside of MAPK pathway activation. Thus, we performed TurboID to differentiate the interactome between wild-type BRAF and BRAFV600E. We identified novel interacting partners of normal vs. BRAFV600E, most strikingly being the tumor suppressor TP53. While TP53 is commonly altered or lost across many malignancies, it is notable that TP53 alterations are rare in melanoma. Our studies suggest that BRAFV600E can interact with and inactivate TP53, thus providing potential mechanistic explanation as to why TP53 inactivation or loss is infrequent in BRAFV600E-driven melanoma.

cancer biology↗

bioRxiv2025

HNF4α controls growth, identity and response to KRAS inhibition of invasive mucinous adenocarcinoma of the lung

Cellular plasticity is a hallmark of cancer, enabling tumor cells to alter identity and evade therapeutic pressure. In invasive mucinous adenocarcinoma of the lung (IMA), NKX2-1 loss triggers a pulmonary to gastric switch marked by aberrant activation of HNF4, a master regulator of gastrointestinal/hepatic differentiation. We find that HNF4 promotes IMA growth and activates a gastric pit cell-like program. Hnf4a deletion induces IMA dedifferentiation, enabling FoxA1/2 to access de novo sites and activate alternative identities. HNF4 also induces a mucinous program associated with tolerance to KRAS blockade, and HNF4 loss enhances response to KRASG12D inhibition. Mechanistically, HNF4 blocks cell cycle exit in drug-tolerant persister cells and promotes activity of the antioxidant transcription factor NRF2. NRF2 activation partially rescues effects of Hnf4a deletion on KRASG12D inhibition, whereas NRF2 inhibition enhances sensitivity to KRASG12D blockade. Thus, HNF4 is a key regulator of identity and primary response to KRASG12D inhibition in IMA. SIGNIFICANCEIMA is a genetically and epigenetically distinct LUAD subtype for which targeted therapies are lacking due to the high proportion of KRAS mutations. This study points to blockade of the HNF4 -> NRF2 axis as a potential strategy to enhance primary response to KRAS inhibition in IMA.

cancer biology↗

bioRxiv2024

Opposing lineage specifiers induce a pro-tumor hybrid-identity state in lung adenocarcinoma

The ability of cancer cells to alter their identity, known as lineage plasticity, is crucial for tumor progression and therapy resistance. In lung adenocarcinoma (LUAD), tumor progression is characterized by a gradual loss of lineage fidelity and the emergence of non-pulmonary identity programs. This can lead to hybrid-identity (hybrid-ID) states in which developmentally incompatible identity programs are co-activated within individual cells. However, the molecular mechanisms underlying these identity shifts remain incompletely understood. Here, we identify the gastrointestinal (GI) transcriptional regulator HNF4 as a critical driver of tumor growth and proliferation in KRAS-driven LUAD. In LUAD cells that express the lung lineage specifier NKX2-1, HNF4 can induce a GI/liver-like state by directly binding and activating its canonical targets. HNF4 also forms an aberrant protein complex with NKX2-1, which disrupts NKX2-1 localization and dampens pulmonary identity within hybrid-ID LUAD. Sustained signaling through the RAS/MEK pathway is critical for maintaining the hybrid-ID state. Moreover, RAS/MEK inhibition augments NKX2-1 chromatin binding at pulmonary-specific genes and induces resistance-associated pulmonary signatures. Finally, we demonstrate that HNF4 depletion enhances sensitivity to pharmacologic KRASG12D inhibition. Collectively, our data show that co-expression of opposing lineage specifiers leads to a hybrid identity state that can drive tumor progression and dictate response to targeted therapy in LUAD.

cancer biology↗

bioRxiv2021

FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma

Changes in cellular identity (also known as histologic transformation or lineage plasticity) can drive malignant progression and resistance to therapy in multiple types of cancer, including lung adenocarcinoma (LUAD). The lineage specifying transcription factors FoxA1 and FoxA2 (FoxA1/2) regulate identity in NKX2-1/TTF1-negative LUAD. However, their role in NKX2-1-positive LUAD has not been systematically investigated. We find that Foxa1/2 knockout severely impairs tumorigenesis in KRAS-driven genetically engineered mouse models and human cell lines. Foxa1/2 deletion leads to the collapse of a dual identity state, marked by co-expression of pulmonary and gastrointestinal transcriptional programs, which has been implicated in LUAD progression. Mechanistically, loss of FoxA1/2 leads to aberrant NKX2-1 activity and genomic localization, which inhibits tumorigenesis and drives alternative cellular identity programs associated with non-proliferative states. This work demonstrates that FoxA1/2 expression is a novel lineage-specific vulnerability in NKX2-1-positive LUAD and identifies mechanisms of response and resistance to targeting FoxA1/2 in this disease.

cancer biology↗

bioRxiv2021

NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity

Lung cancer remains a leading cause of cancer death, with unclear mechanisms driving the transition to aggressive cancer with poor prognosis. The RAS[->]RAF[->]MEK[->]ERK pathway is hyper-activated in [~]50% of human lung adenocarcinoma (LUAD). An initial activating mutation induces homeostatic feedback mechanisms that limit ERK activity. Additional, undefined genetic hits overcome the feedback, leading to high ERK activity that drives malignant progression. At detection, the majority of LUADs express the homeobox transcription factor NKX2-1, which also limits malignant progression. NKX2-1 constrains LUAD, in part, by maintaining a well-differentiated state with features of pulmonary identity. We asked if loss of NKX2-1 might also contribute to the release of ERK activity that drives tumor progression. Using human tissue samples and cell lines, xenografts, and genetic mouse models, we show that NKX2-1 induces the ERK phosphatase DUSP6. In tumor cells from late-stage LUAD with silenced NKX2-1, re-introduction of NKX2-1 induces DUSP6 and inhibits cell proliferation and migration and tumor growth and metastasis. CRISPR knockout studies show that DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo. Further, DUSP6 expression is sufficient to inhibit RAS-driven LUAD. We conclude that NKX2-1 silencing, and thereby DUSP6 downregulation, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression.

cancer biology↗

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↗