In a groundbreaking study published in Nature, researchers have unveiled the intricate interplay between genetic alterations and the cell of origin in shaping the fate of small-cell lung cancer (SCLC). This work offers profound insights into how the loss of the tumor suppressor gene PTEN and amplification of the oncogene MYC cooperate to drive a specific SCLC subtype characterized by tuft cell features, known as SCLC-P. The findings provide a pivotal framework for understanding lineage plasticity in lung cancer and highlight potential therapeutic targets for a notoriously aggressive malignancy.
Small-cell lung cancer is a formidable neuroendocrine tumor with distinct molecular subtypes defined by differential expression of transcription factors such as ASCL1 and POU2F3. While MYC amplification has been long associated with poor prognosis and aggressive tumor behavior, the relationship between MYC, PTEN loss, and the resulting phenotypic heterogeneity in SCLC has remained obscure. This latest study bridges that gap by revealing that PTEN loss preferentially drives the emergence of POU2F3-high tumors, a shift marked by upregulated MYC and depletion of ASCL1 expression.
The researchers began by meticulously analyzing a cohort of 112 human SCLC tumors, stratifying them based on POU2F3 expression levels. They discovered that PTEN deletion was significantly more prevalent in POU2F3-high tumors, occurring in 63% of cases compared with only 27% in POU2F3-low tumors. This statistically significant finding (P < 0.009) suggests a tight genetic linkage between PTEN loss and the SCLC-P subtype, which features tuft cell-like characteristics. Importantly, this correlation provides a genetic basis to previously observed phenotypic differences within SCLC subgroups, emphasizing the role of PTEN in the tumor lineage landscape.
To experimentally validate these observations, the team utilized CRISPR-Cas9 gene editing to knockout PTEN in basal organoids derived from RPM and RPMA mouse models. RPM tumors are characterized by the expression of ASCL1, whereas RPMA tumors lack ASCL1 and express YAP1, resembling human SCLC-P. PTEN loss in these models led to accelerated tumor growth, confirming PTEN’s role as a potent tumor suppressor in lung cancer. Intriguingly, while YAP1 and ASCL1 expression remained stable following PTEN deletion, POU2F3 expression markedly increased in both organoid types, underscoring PTEN loss as a driver of the tuft cell-like SCLC phenotype.
Immunohistochemistry analyses of RPMA tumors with PTEN deletion revealed increased POU2F3 expression near-uniformly across tumor cells. The elevation of POU2F3 correlated closely with phospho-AKT levels—signifying activated PI3K/AKT signaling pathways downstream of PTEN loss—and inversely correlated with NEUROD1, another neuroendocrine lineage marker. This inverse relationship indicates that PTEN loss not only enhances SCLC-P features but seemingly suppresses alternate neuroendocrine fates, specifically the SCLC-N subtype characterized by NEUROD1 expression.
Beyond the molecular phenotype, PTEN-deleted RPMA tumors exhibited striking histological heterogeneity, comprising regions of adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma interspersed within predominantly small-cell histology. Notably, these non-small cell lung cancer (NSCLC) regions were enriched for basal cell markers KRT5 and P63, suggesting a lineage drift influenced by PTEN loss and MYC activity. This phenotypic plasticity mirrors clinical observations where SCLC-P can be found adjacent to squamous cell carcinoma in combined SCLC, implying possible transitional states between these histologies.
The emergence of squamous-like and tuft-like features within the same tumors raises compelling questions about the role of ASCL1 deficiency in facilitating divergent lineage choices under MYC and AKT signaling pressure. Since squamous cell carcinomas often originate from basal cells and exhibit active MYC and PI3K/AKT pathways, the results suggest that ASCL1 status might gate the cellular trajectory toward either neuroendocrine tuft cells or squamous epithelial differentiation. This finding not only enriches the biological understanding of SCLC heterogeneity but also opens avenues for lineage-targeted therapies.
Further supporting these conclusions, the authors employed genetically engineered mouse models (GEMMs) and demonstrated that induction of lung cancer through K5-Cre recombinase in the presence of PTEN loss favored POU2F3-high tumor development. Tumors from these mice displayed a robust correlation between MYC and POU2F3 expression, reinforcing the cooperative effect of MYC amplification and PTEN deficiency in driving SCLC-P fate. Conversely, tumors with lower MYC levels expressed less POU2F3, emphasizing the dose-dependent nature of the genetic interplay.
Immunohistochemistry for subtype markers in K5-Cre-induced tumors further revealed that high-MYC regions aligned with POU2F3 positivity, whereas low-MYC regions were devoid of this expression. This regional heterogeneity within tumors highlights the spatial dynamics of transcription factor expression and lineage commitment during tumor progression. It also suggests that therapeutic strategies modulating MYC or its downstream effectors could adjust tumor cell fate and sensitivity to treatment.
From a broader perspective, this study exemplifies how precise genomic edits in defined cell populations can clarify the contribution of genetic drivers to tumor lineage choice and plasticity. The use of basal cell-derived organoids and animal models allowed the authors to dissect the cell-intrinsic effects of genetic alterations, minimizing confounding influences such as tumor microenvironment variability. This approach advances the field toward more sophisticated models of tumor heterogeneity that better recapitulate human disease.
Clinically, the link between PTEN loss and the SCLC-P subtype carries profound implications. The SCLC-P subtype tends to resist traditional neuroendocrine-targeted therapies, and its connection to hyperactivated PI3K/AKT signaling suggests that targeting this pathway might yield therapeutic benefits. Moreover, the coexistence of tuft-like and squamous-like tumors within single lesions calls for reassessment of diagnostic criteria and therapeutic regimens, advocating for personalized treatments based on detailed molecular profiling.
In sum, this comprehensive investigation sheds light on the molecular underpinnings of SCLC subtype specification, revealing that the intersection of PTEN loss, MYC gain, and cell of origin decisively sculpts tumor phenotype and behavior. The consequent model of lineage plasticity not only advances fundamental cancer biology but also equips clinicians with new conceptual tools to tackle one of the deadliest lung cancers with tailored strategies.
As research continues to unravel the complexities of lung cancer subtypes, studies like this illuminate the path toward precision oncology, where understanding the genetic and cellular context of tumors enables more effective and less toxic therapies. The elucidation of PTEN and MYC’s convergent roles in defining neuroendocrine tuft lineage features marks a paradigm shift, highlighting the plasticity inherent in cancer cells and the potential to intercept malignant evolution by modulating lineage fate.
Subject of Research:
Small-cell lung cancer lineage plasticity driven by genetic alterations and cell of origin.
Article Title:
Basal cell of origin resolves neuroendocrine–tuft lineage plasticity in cancer.
Article References:
Ireland, A.S., Xie, D.A., Hawgood, S.B. et al. Basal cell of origin resolves neuroendocrine–tuft lineage plasticity in cancer. Nature (2025). https://doi.org/10.1038/s41586-025-09503-z
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Tags: aggressive malignancies and prognosisBasal cell involvement in cancergenetic alterations in cancerlineage plasticity in lung cancerMYC oncogene amplificationneuroendocrine tumor subtypesphenotypic heterogeneity in tumorsPTEN tumor suppressor geneSCLC-P tuft cell featuressmall cell lung cancer researchtherapeutic targets for SCLCtranscription factors in lung cancer
