Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer DOI Creative Commons
Abbie S. Ireland,

Sarah B. Hawgood,

Dong Xie

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 15, 2024

Summary paragraph Neuroendocrine and tuft cells are rare, chemosensory epithelial lineages defined by expression of ASCL1 POU2F3 transcription factors, respectively 1,2 . cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes 3–13 The mechanisms driving neuroendocrine–tuft tumour heterogeneity, the origins cancers unknown. Using multiple genetically-engineered animal models SCLC, we demonstrate that basal origin (but not accepted neuroendocrine origin) generates neuroendocrine–tuft-like tumours highly recapitulate human SCLC. Single-cell clonal analyses basal-derived SCLC further uncovers unexpected transcriptional states lineage trajectories underlying plasticity. Uniquely in cells, introduction genetic alterations enriched high MYC, PTEN loss, suppression, cooperate promote tumours. Transcriptomics 944 SCLCs reveal basal-like subset tuft-ionocyte-like state altogether remarkable conservation between normal injury response 14–18 Together, these data suggest is plausible for other neuroendocrine-tuft can explain heterogeneity—offering new insights targeting

Язык: Английский

Cancer plasticity in therapy resistance: Mechanisms and novel strategies DOI

Xing Niu,

Wenjing Liu,

Zhang Yinling

и другие.

Drug Resistance Updates, Год журнала: 2024, Номер 76, С. 101114 - 101114

Опубликована: Июнь 22, 2024

Язык: Английский

Процитировано

16
Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies DOI Creative Commons

Tongchen He,

Lanbo Xiao, Yuanyuan Qiao

и другие.

Cancer Cell, Год журнала: 2024, Номер 42(8), С. 1336 - 1351.e9

Опубликована: Июль 18, 2024

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of tuft cell lineage and cell-like small lung cancer (SCLC). Here, we identify a specific dependence POU2F3 molecular subtype SCLC (SCLC-P) on activity mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment SCLC-P cells with proteolysis targeting chimera (PROTAC) degrader mSWI/SNF ATPases evicts its coactivators from attenuates downstream signaling. B malignancies which are dependent POU2F1/2 cofactor, POU2AF1, also sensitive to ATPase degraders, treatment leading eviction POU2AF1 IRF4 decreased signaling in multiple myeloma cells. An orally bioavailable significantly inhibits tumor growth preclinical models without signs toxicity. This study suggests that POU2F-POU2AF-driven have an intrinsic complex, representing therapeutic vulnerability.

Язык: Английский

Процитировано

15
The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1 DOI Creative Commons
Rodrigo Romero, Tinyi Chu, Tania J González-Robles

и другие.

Nature Cancer, Год журнала: 2024, Номер 5(11), С. 1641 - 1659

Опубликована: Окт. 11, 2024

Abstract Lineage plasticity is a hallmark of cancer progression that impacts therapy outcomes, yet the mechanisms mediating this process remain unclear. Here, we introduce versatile in vivo platform to interrogate neuroendocrine lineage transformation throughout prostate progression. Transplanted mouse organoids with human-relevant driver mutations ( Rb1 − / ; Trp53 cMyc + or Pten ) develop adenocarcinomas, but only those deletion advance aggressive, ASCL1 (NEPC) resistant androgen receptor signaling inhibitors. Notably, transition requires an microenvironment not replicated by conventional organoid culture. Using multiplexed immunofluorescence and spatial transcriptomics, reveal cells arise from KRT8 luminal cells, progressing into transcriptionally heterogeneous ;KRT8 NEPC. Ascl1 loss established NEPC causes transient regression followed recurrence, its before transplantation abrogates plasticity, resulting castration-sensitive adenocarcinomas. This dynamic model highlights importance timing offers identify additional drivers.

Язык: Английский

Процитировано

12
Molecular subtypes of neuroendocrine carcinomas: A cross-tissue classification framework based on five transcriptional regulators DOI
Zhanyu Wang, Chengming Liu,

Sufei Zheng

и другие.

Cancer Cell, Год журнала: 2024, Номер 42(6), С. 1106 - 1125.e8

Опубликована: Май 23, 2024

Язык: Английский

Процитировано

11
Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation DOI Creative Commons
Mona Teng, Jiacheng Guo, Xin Xu

и другие.

Cancer Cell, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Circular RNA (circRNA) is a class of noncoding with regulatory potentials. Its role in the transdifferentiation prostate and lung adenocarcinoma into neuroendocrine cancer (NEPC) small cell (SCLC) remains unexplored. Here, we identified circRMST as an exceptionally abundant circRNA predominantly expressed NEPC SCLC, strong conservation between humans mice. Functional studies using shRNA, siRNA, CRISPR-Cas13, Cas9 consistently demonstrate that essential for tumor growth expression ASCL1, master regulator fate. Genetic knockout Rmst genetic engineered mouse models prevents transdifferentiation, maintaining tumors state. Mechanistically, physically interacts lineage transcription factors NKX2-1 SOX2. Loss induces protein degradation through autophagy-lysosomal pathway alters genomic binding SOX2, collectively leading to loss ASCL1 transcription.

Язык: Английский

Процитировано

1
Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer DOI Creative Commons
John B. Finlay, Abbie S. Ireland,

Sarah B. Hawgood

и другие.

Cancer Cell, Год журнала: 2024, Номер 42(6), С. 1086 - 1105.e13

Опубликована: Май 23, 2024

The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to neuroblastoma (ONB), a rare tumor of unclear origins. Employing alterations in Rb1/Trp53/Myc (RPM), we establish genetically engineered mouse model high-grade metastatic ONB exhibiting NEUROD1

Язык: Английский

Процитировано

6
CUL4B regulates thyroid cancer differentiation and treatment sensitivity by ubiquitinating ARID1A DOI

Haiyan Gu,

Bo Han, Jing Hu

и другие.

Translational Oncology, Год журнала: 2025, Номер 56, С. 102389 - 102389

Опубликована: Апрель 11, 2025

Язык: Английский

Процитировано

0
Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies DOI Creative Commons

Tongchen He,

Lanbo Xiao, Yuanyuan Qiao

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 25, 2024

SUMMARY The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of tuft cell lineage and cell-like small lung cancer (SCLC). Here, we found that POU2F3 molecular subtype SCLC (SCLC-P) exhibits an exquisite dependence on activity mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P lines were sensitive to nanomolar levels a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared other subtypes SCLC. its cofactors interact with components was evicted from upon degradation, leading attenuation downstream oncogenic signaling in cells. A novel, orally bioavailable PROTAC degrader, AU-24118, demonstrated preferential efficacy relative SCLC-A significantly decreased tumor growth preclinical models. AU-24118 did not alter normal numbers or colon, nor it exhibit toxicity mice. B malignancies which displayed dependency POU2F1/2 cofactor, POU2AF1 (OCA-B), also remarkably degradation. Mechanistically, treatment multiple myeloma cells compacted chromatin, dislodged IRF4, IRF4 signaling. In POU2AF1-dependent, disseminated murine model myeloma, enhanced survival pomalidomide, approved for myeloma. Taken together, our studies suggest POU2F-POU2AF-driven have intrinsic complex, representing therapeutic vulnerability.

Язык: Английский

Процитировано

3
PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity DOI Open Access

Grigor Varuzhanyan,

Chia‐Chun Chen, Jack Freeland

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 13, 2024

ABSTRACT Adenocarcinomas from multiple tissues can evolve into lethal, treatment-resistant small cell neuroendocrine (SCN) cancers comprising subtypes with poorly defined metabolic characteristics. The role of metabolism in directly driving subtype determination remains unclear. Through bioinformatics analyses thousands patient tumors, we identified enhanced PGC-1α—a potent regulator oxidative phosphorylation (OXPHOS)—in various SCN (SCNCs), closely linked differentiation. In a patient-derived prostate tissue SCNC transformation system, the ASCL1-expressing showed elevated PGC-1α expression and increased OXPHOS activity. Inhibition reduced proliferation lung cancer lines blocked tumor formation. Conversely, enhancing PGC- 1α OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled formation rate promoted commitment to ASCL1 lineage. These results establish as driver progression determination, highlighting novel vulnerabilities SCNCs across different tissues. STATEMENT OF SIGNIFICANCE Our study provides functional evidence that reprogramming impact phenotypes establishes PGC-1α-induced lineage determination. mechanistic insights reveal common originating tissues, opening new avenues for pan-SCN therapeutic strategies.

Язык: Английский

Процитировано

3
Mechanisms governing lineage plasticity and metabolic reprogramming in cancer DOI Creative Commons
Lillian M. Perez,

Smrruthi V. Venugopal,

Anna St Martin

и другие.

Trends in cancer, Год журнала: 2024, Номер unknown

Опубликована: Авг. 1, 2024

Dynamic alterations in cellular phenotypes during cancer progression are attributed to a phenomenon known as 'lineage plasticity'. This process is associated with therapeutic resistance and involves concurrent shifts metabolic states that facilitate adaptation various stressors inherent malignant growth. Certain metabolites also serve synthetic reservoirs for chromatin modification, thus linking epigenetic regulation. There remains critical need understand the mechanisms converge on lineage plasticity reprogramming prevent emergence of lethal disease. review attempts offer an overview our current understanding interplay between context cancer, highlighting intersecting drivers hallmarks, emphasis solid tumors.

Язык: Английский

Процитировано

3