bims-necame 2026-03-29 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2026–03–29
eight papers selected by
Grigor Varuzhanyan, UCLA

Investigating Metabolically Altered Pathways in Small Cell Lung Cancer: From RNA Sequencing Analysis to Seahorse-Based Functional Validation.
C4orf3 Regulates HIF-1α Degradation Under Hypoxic Conditions and Contributes to the Malignant Phenotype in Small Cell Lung Cancer.
SMARCA4 promotes lineage plasticity and enzalutamide resistance in prostate cancer by regulating PROX1 via H3K27 acetylation.
The oncogene c-MYC: an orchestrator of the tumor microenvironment and drug sensitivity in small cell lung cancer.
LSD1 inhibitor, TAS1440, disrupts INSM1-LSD1 complex activating tumor-suppressive pathways via transcriptional reprogramming in neuroendocrine SCLC.
Paired-sample Analysis of ERG Expression and TMPRSS2-ERG Fusion in Treatment-induced Neuroendocrine Prostate Cancer.
Molecular subtyping of small-cell lung cancer in clinical practice: Primary tumor-lymph node concordance, intratumoral heterogeneity, and genomic context in a Chinese cohort.
ATM functions as a rheostat of metabolic stress in small-cell lung cancer.

Methods Protoc. 2026 Mar 10. pii: 46. [Epub ahead of print]9(2):

Investigating Metabolically Altered Pathways in Small Cell Lung Cancer: From RNA Sequencing Analysis to Seahorse-Based Functional Validation.

Subhadeep Das, Sagar M Utturkar, Roshnee Bose, Elizabeth J Tran.

  Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid progression, early metastasis, and high relapse rates due to acquired chemoresistance. The human DEAD-box RNA helicase DDX5 is overexpressed in SCLC and has recently gained attention as a viable therapeutic target. Supinoxin (RX-5902), a selective small-molecule inhibitor of DDX5, exhibits strong anti-tumor activity. Recent evidence suggests that its cytotoxic effects are mediated through the disruption of mitochondrial respiration. In this study, transcriptomic profiling via RNA sequencing (RNA-seq) revealed significant downregulation of genes involved in cellular respiration following Supinoxin treatment and DDX5 knockdown in chemoresistant H69AR cells. To functionally validate these findings, we employed the Seahorse XF Cell Mito Stress Test, which measures key parameters of mitochondrial bioenergetics through oxygen consumption rate (OCR) analysis. Supinoxin-treated cells exhibited marked mitochondrial dysfunction, supporting the hypothesis that DDX5 inhibition disrupts cellular energy metabolism. These findings illuminate a previously underappreciated role of DDX5 in mitochondrial regulation and offer mechanistic insights into Supinoxin's cytotoxic effects, underscoring its potential as a targeted therapy in SCLC.

Keywords:  DEAD-box helicase 5 (DDX5); RNA sequencing; Seahorse XF Cell Mito Stress Test; mitochondrial dysfunction; small cell lung cancer

DOI:  https://doi.org/10.3390/mps9020046
J Cancer. 2026 ;17(3): 457-468

C4orf3 Regulates HIF-1α Degradation Under Hypoxic Conditions and Contributes to the Malignant Phenotype in Small Cell Lung Cancer.

Keita Sakanashi, Hideya Onishi, Naoya Iwamoto, Yoshiyuki Nakanishi, Shinsaku Itoyama, Shogo Masuda, Keigo Ozono, Kosuke Yanai, Katsuya Nakamura, Masayo Nagami, Kenichi Nishiyama, Masayuki Kojima, Yoshinao Oda, Masafumi Nakamura.

Hypoxia is a critical feature of the tumour microenvironment in small cell lung cancer (SCLC) and contributes to malignant progression through hypoxia-inducible factor 1 alpha (HIF-1α)-mediated transcriptional programs. However, the upstream regulators that maintain HIF-1α stability under hypoxic conditions remain incompletely understood. In this study, we identified the chromosome 4 open reading frame 3 (C4orf3) as a hypoxia-inducible gene and investigated its functional significance in SCLC. C4orf3 expression is upregulated under hypoxic conditions, and its knockdown suppresses cell proliferation, migration, and invasion in vitro and reduces tumour growth in vivo. Mechanistically, C4orf3 depletion decreased HIF-1α protein levels even under chemically induced hypoxia, suggesting that its regulation is independent of the canonical PHD-VHL degradation pathway. Further analysis demonstrated that C4orf3 modulates HIF-1α stability through PIASy-mediated SUMOylation. Clinical relevance was supported by a positive association between C4orf3 and HIF-1α expression in resected SCLC tissues. These findings suggested that C4orf3 functions as a regulator of hypoxic adaptation in SCLC by maintaining HIF-1α stability and may represent a potential therapeutic target in hypoxia-driven tumour progression.

DOI: https://doi.org/10.7150/jca.127942
Cell Death Discov. 2026 Mar 25.

SMARCA4 promotes lineage plasticity and enzalutamide resistance in prostate cancer by regulating PROX1 via H3K27 acetylation.

Chenwei Wu, Mayao Luo, Chaojian Wu, Yi Yuan, Yadong Li, Yuanpeng Liao, Yifan Zhang, Xin Huang, Mengqi Wang, Shidong Lv, Qiang Wei.

Enzalutamide resistance is a dynamic process often culminating in the aggressive progression to neuroendocrine prostate cancer (NEPC). This lineage plasticity is hypothesized to be driven by underlying epigenetic alterations, yet the core molecular drivers remain unclear. Elucidating these factors is of significant clinical importance for overcoming resistance. To model this transition, we established a dynamic gradient-resistant cell model simulating the clinical response to enzalutamide, and found robust upregulation of the chromatin remodeling factor SMARCA4 in resistant cells. Both in vitro and in vivo experimental results demonstrated that inhibiting SMARCA4 effectively suppresses tumor progression and reverses neuroendocrine transformation. Mechanistically, integrated multi-omics analysis, correlation studies, and protein interaction experiments revealed the transcription factor PROX1 as a crucial downstream target of SMARCA4, where its inhibition alone was sufficient to reverse the aggressive malignancy and neuroendocrine characteristics of resistant cells. We further demonstrated that SMARCA4 enhances H3K27ac levels and chromatin accessibility at the PROX1 locus to regulate its expression. Importantly, the tumor-suppressive effect of SMARCA4 knockdown could be rescued by histone deacetylase inhibitors (HDACi), achieving a level of recovery comparable to PROX1 overexpression. In summary, this study defines a core epigenetic pathway, showing that increased SMARCA4 activity promotes luminal-to-neuroendocrine transformation by enhancing histone acetylation and chromatin accessibility at the PROX1 locus. Targeting the SMARCA4-PROX1 axis provides a valuable therapeutic strategy for combating enzalutamide resistance and NEPC progression.

DOI: https://doi.org/10.1038/s41420-026-03068-0
Crit Rev Oncol Hematol. 2026 Mar 24. pii: S1040-8428(26)00182-4. [Epub ahead of print] 105295

The oncogene c-MYC: an orchestrator of the tumor microenvironment and drug sensitivity in small cell lung cancer.

Peiyan Zhao, Qi Wang, Xinyue Wang, Lin Tian, Yan Liu, Hui Li, Haifeng Liu.

  Small-cell lung cancer (SCLC) is widely recognized as a notoriously refractory tumor, characterized by rapid proliferation, high aggressiveness, and early metastasis. Although immunotherapy combined with chemotherapy has become the standard of care for patients with extensive-stage SCLC, significant unmet needs, especially referring to lack of targeted therapy, persist in the clinic. The c-MYC proto-oncogene, one of the critical oncogenes, has been shown to be heavily associated with malignant tumor growth and drug resistance. c-MYC is amplified in SCLC and is further implicated in SCLC phenotypic plasticity, immune microenvironment composition, metabolic reprogramming, and therapy vulnerability, thereby playing the most key role in SCLC recurrence and devastating survival outcomes. This review summarized current knowledge on the mechanisms by which c-MYC regulates the SCLC oncogenic network and the status of drug development efforts targeted c-MYC. We also explore in detail that targeting c-Myc protein directly or indirectly represents a promising strategy for novel SCLC therapies.

Keywords:  c-MYC; drug resistance; small-cell lung cancer; targeting therapy

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105295
Nat Commun. 2026 Mar 25.

LSD1 inhibitor, TAS1440, disrupts INSM1-LSD1 complex activating tumor-suppressive pathways via transcriptional reprogramming in neuroendocrine SCLC.

Takumitsu Machida, Yingbo Gong, Sayaka Tsukioka, Atsushi Onodera, Akitoshi Nakayama, Naoko Hashimoto, Takahiro Fuchigami, Motoi Nishimura, Tomohiro Ogino, Ryota Kurimoto, Yasufumi Uematsu, Hidemi Suzuki, Hongye Yu, Mingyang Chen, Masataka Yokoyama, Ikki Sakuma, Yuki Taki, Takashi Kono, Takashi Miki, Shinichiro Motohashi, Yusuke Kawashima, Osamu Ohara, Satoshi Yamashita, Tatsuya Suzuki, Ryo Hatanaka, Yasuo Kodama, Shuichi Ohkubo, Tomoaki Tanaka.

Small cell lung cancer (SCLC) is aggressive with limited treatment options, requiring new therapies. Lysine-specific histone demethylase 1 A (LSD1) maintains neuroendocrine state by repressing NOTCH/TGF-β signaling; their reactivation suppresses proliferation and induces differentiation. However, mechanisms of LSD1 inhibition and chemoresistance remain unclear. Here we developed TAS1440, a histone H3-competitive LSD1 inhibitor, using structure-based engineering to improve specificity and reduce off-target effects. Unlike irreversible inhibitors targeting the flavin adenine dinucleotide site, TAS1440 non-covalently targets the H3-binding pocket to enhance safety and efficacy. TAS1440 suppressed proliferation in INSM1/ASCL1-high SCLC-A cells and induced tumor regression in xenografts. TAS1440 acts through dual mechanisms: inhibiting LSD1 activity and disrupting LSD1-repressive complexes, remodeling histone marks and activating transcription factors INSM1 and SMAD2. These actions reprogram tumor-suppressive TGF-β/NOTCH signaling, supporting TAS1440 as epigenetic therapy for SCLC. Loss of LSD1 enzymatic activity or INSM1 knockout abrogated TAS1440 effects, defining its mode of action and chemoresistance. These findings support TAS1440 as a next-generation epigenetic therapy candidate for INSM1-high SCLC-A.

DOI: https://doi.org/10.1038/s41467-026-70984-1
Anticancer Res. 2026 Apr;46(4): 1929-1942

Paired-sample Analysis of ERG Expression and TMPRSS2-ERG Fusion in Treatment-induced Neuroendocrine Prostate Cancer.

Chu-shikoku Japan Urological Consortium (CsJUC) Research Collaboration

   BACKGROUND/AIM: Prostate cancer is one of the most common malignancies in men. Although androgen deprivation therapy (ADT) offers substantial benefit, resistance to androgen signaling ultimately develops, leading to castration-resistant prostate cancer (CRPC). Approximately 10-17% of CRPC cases evolve into treatment-induced neuroendocrine prostate cancer (t-NEPC), an aggressive, androgen receptor (AR)-independent subtype. The TMPRSS2-ERG fusion gene is among the most frequent genomic alterations in prostate cancer; however, its involvement in t-NEPC development remains unclear.
PATIENTS AND METHODS: We retrospectively analyzed nine Japanese cases of t-NEPC diagnosed across multiple institutions. Immunohistochemical staining for AR and ERG and RT-PCR for TMPRSS2-ERG fusion gene expression were performed on paired adenocarcinoma and t-NEPC samples. Clinical data - including prostate specific antigen levels, Gleason scores, metastatic patterns, and outcomes - were compared between ERG-positive and ERG-negative groups.
RESULTS: ERG-positive prostate cancer was found in three of nine cases (33.3%), all of which were AR-positive, indicating that active AR signaling is required for TMPRSS2-ERG expression. ERG positivity was not clearly associated with prognosis or drug sensitivity, but time to NEPC differentiation tended to be shorter in ERG-positive cases. Only the e1e4 isoform of TMPRSS2-ERG was detected, while e2e4 was absent.
CONCLUSION: This study highlights heterogeneity in TMPRSS2-ERG fusion dynamics during t-NEPC evolution and suggests a potential association between ERG expression and earlier NE differentiation. This study provides a rare opportunity to analyze paired pre- and post-NEPC tissues, offering valuable insight into the relationship between ERG and TMPRSS2-ERG fusion gene expression and clinical parameters.

Keywords:  AR-pathway positive prostate cancers (ARPC); ERG expression; TMPRSS2-ERG fusion gene; treatment induced NEPC (t-NEPC)

DOI:  https://doi.org/10.21873/anticanres.18085
Lung Cancer. 2026 Mar 21. pii: S0169-5002(26)00438-1. [Epub ahead of print]215 109377

Molecular subtyping of small-cell lung cancer in clinical practice: Primary tumor-lymph node concordance, intratumoral heterogeneity, and genomic context in a Chinese cohort.

Zhihong Lin, Qiong Lyu, Jiawei Li, Lei Fan, Ping Wang, Yue Wu, Xiaodong Lin, Ping He.

  We evaluated the immunohistochemical expression of ASCL1, NEUROD1, POU2F3, YAP1, INSM1, NFIB, SLFN11, and CASP10 in 94 resected primary small-cell lung cancer (SCLC) tumors and 32 matched regional lymph-node metastases (excluding combined SCLC and micro-metastases). We applied subtype assignments (SCLC-A, SCLC-N, SCLC-A/N, SCLC-P, SCLC-I), quantified intratumoral heterogeneity using Shannon Evenness Index, and assessed genomic alterations through targeted next-generation sequencing. Subtypes were dominated by ASCL1- and NEUROD1-driven programs, with one-third of tumors exhibiting mixed A/N expression. Cross-site comparison showed moderate concordance between primary tumors and lymph-node metastases; however, notable phenotypic discordance occurred in matched pairs (37.5%), frequently manifesting as a drift toward NEUROD1-dominant or mixed A/N phenotypes following dissemination. NEUROD1 correlated strongly with NFIB and INSM1, and NEUROD1 expression was high in paired regional lymph node metastases, supporting migratory or plastic phenotype associations. SLFN11 demonstrated high concordance between primary tumors and matched regional lymph node metastases, reinforcing its reliability as a predictive biomarker for chemotherapy sensitivity, owing to its stable expression during initial lymphatic dissemination. CASP10 was markedly downregulated in tumors relative to that in normal lung or lymphoid tissues. Genomic profiling confirmed canonical TP53/RB1 dual inactivation pattern alongside recurrent alterations in NOTCH1, PIK3CA, CREBBP, and KMT2D. Thus, SCLC subtyping shows significant spatiotemporal heterogeneity and organ-specific lineage plasticity. The observed discordance during regional nodal dissemination suggests that single site-dependent immunohistochemistry-based subtyping may be insufficient. Future frameworks incorporating multi-region analysis and liquid biopsy are essential to capture the dynamic evolution of SCLC and optimize personalized management for localized disease.

Keywords:  Immunohistochemistry; Intratumoral heterogeneity; Lymph-node metastasis; Molecular subtyping; NFIB; SLFN11; Small-cell lung cancer

DOI:  https://doi.org/10.1016/j.lungcan.2026.109377
bioRxiv. 2026 Mar 17. pii: 2026.03.13.711672. [Epub ahead of print]

ATM functions as a rheostat of metabolic stress in small-cell lung cancer.

Debdatta Halder, Utsav Sen, Vrinda Jethalia, Subhamoy Chakraborty, Andrew Elliott, Kedwin Ventura, Ari Vanderwalde, Balazs Halmos, Hossein Borghaei, Tin Htwe Thin, Alan Soto, Mirela Berisa, Rachel Brody, Deniz Demircioglu, Dan Hasson, Triparna Sen.

ATM is best known as a guardian of genomic stability, yet its contributions to oncogenic signaling in aggressive malignancies like small-cell lung cancer (SCLC) remain poorly understood. Despite ATM being an established clinical vulnerability in SCLC, its influence on dysregulated tumorigenic circuits remains unclear. We demonstrate that inhibition of ATM disrupts the AKT-mTORC1-4EBP1 signaling axis, leading to attenuation of the master regulator of stress, ATF4. ATF4 and MYC appear to co-regulate one another in a feedback loop critical for redox homeostasis. ATM inhibition perturbs both the expression and function of MYC and ATF4, leading to increased intracellular reactive oxygen species, impaired glutathione recycling, and ferroptotic cell death, thereby exposing a crucial dependency of SCLC on stress-adaptive signaling. We uncover previously unrecognized metabolic vulnerability in SCLC, nominating ATM as a regulator of adaptive stress, expanding its role beyond canonical DNA damage repair (DDR) and highlighting therapeutically exploitable opportunities in aggressive tumors.
Statement of Significance: The metabolic landscape of SCLC remains poorly characterized, particularly its interaction with dysregulated signaling networks, limiting the development of effective strategies to overcome therapeutic resistance. Our work reveals an expanded role for ATM beyond DNA repair, positioning it as a key regulator of metabolic rewiring and highlighting new therapeutic opportunities for SCLC.

DOI: https://doi.org/10.64898/2026.03.13.711672