Identification and Targeting of Long-Term Tumor-Propagating Cells in Small Cell Lung Cancer

Jahchan, Nadine S.; Lim, Jing Shan; Bola, Becky M.; Morris, Karen; Seitz, Garrett; Tran, Kim Q.T.; Xu, Lei; Trapani, Francesca; Morrow, Christopher J.; Cristea, Sandra; Coles, Garry L.; Yang, Dian; Vaka, Dedeepya; Kareta, Michael S.; George, Julie; Mazur, Paweł K.; Nguyen, Thuyen; Anderson, Wade; Dylla, Scott J.; Blackhall, Fiona; Peifer, Martin; Dive, Caroline; Sage, Julien

doi:10.1016/j.celrep.2016.06.021

Cited by 76 publications

(67 citation statements)

References 65 publications

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“…2 and Supplementary Table 2), observing that 21 of the 29 LS patients with survival o3 years have a high VM ratio. This result is consistent with the hypothesis that VM acts through aggressive tumour 'stem-like' phenotypes, and tumour plasticity 6,37 , leading to worse clinical outcomes. Furthermore, 7 out of the 10 LS patients who survived 45 years, (17% of the total cohort studied) had low VM ratios.…”

Section: Ve-cadherin Knockdown Increases Chemosensitivity In Vivosupporting

confidence: 81%

264 Vasculogenic mimicry in small cell lung cancer

Trapani¹,

Metcalf²,

Polański³

et al. 2014

European Journal of Cancer

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Small cell lung cancer (SCLC) is characterized by prevalent circulating tumour cells (CTCs), early metastasis and poor prognosis. We show that SCLC patients (37/38) have rare CTC subpopulations co-expressing vascular endothelial-cadherin (VE-cadherin) and cytokeratins consistent with vasculogenic mimicry (VM), a process whereby tumour cells form 'endothelial-like' vessels. Single-cell genomic analysis reveals characteristic SCLC genomic changes in both VE-cadherin-positive and -negative CTCs. Higher levels of VM are associated with worse overall survival in 41 limited-stage patients' biopsies (Po0.025). VM vessels are also observed in 9/10 CTC patient-derived explants (CDX), where molecular analysis of fractionated VE-cadherin-positive cells uncovered copy-number alterations and mutated TP53, confirming human tumour origin. VE-cadherin is required for VM in NCI-H446 SCLC xenografts, where VM decreases tumour latency and, despite increased cisplatin intra-tumour delivery, decreases cisplatin efficacy. The functional significance of VM in SCLC suggests VM regulation may provide new targets for therapeutic intervention.

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Section: Ve-cadherin Knockdown Increases Chemosensitivity In Vivosupporting

confidence: 81%

264 Vasculogenic mimicry in small cell lung cancer

Trapani¹,

Metcalf²,

Polański³

et al. 2014

European Journal of Cancer

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“…Advances with targeted therapies are yet to materialise and chemotherapy regimens have remained unchanged for almost three decades5. Improved understanding of SCLC biology is essential to instruct development of improved treatments, for example, by targeting SCLC stem cells6 or overcoming mechanisms of chemotherapy resistance.…”

mentioning

confidence: 99%

Vasculogenic mimicry in small cell lung cancer

et al. 2016

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Small cell lung cancer (SCLC) is characterized by prevalent circulating tumour cells (CTCs), early metastasis and poor prognosis. We show that SCLC patients (37/38) have rare CTC subpopulations co-expressing vascular endothelial-cadherin (VE-cadherin) and cytokeratins consistent with vasculogenic mimicry (VM), a process whereby tumour cells form ‘endothelial-like' vessels. Single-cell genomic analysis reveals characteristic SCLC genomic changes in both VE-cadherin-positive and -negative CTCs. Higher levels of VM are associated with worse overall survival in 41 limited-stage patients' biopsies (P<0.025). VM vessels are also observed in 9/10 CTC patient-derived explants (CDX), where molecular analysis of fractionated VE-cadherin-positive cells uncovered copy-number alterations and mutated TP53, confirming human tumour origin. VE-cadherin is required for VM in NCI-H446 SCLC xenografts, where VM decreases tumour latency and, despite increased cisplatin intra-tumour delivery, decreases cisplatin efficacy. The functional significance of VM in SCLC suggests VM regulation may provide new targets for therapeutic intervention.

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“…Maintenance of cancer-initiating cells and transformation from SCLC to NSCLC have been implicated as mechanisms of chemotherapy resistance (47, 48). Expansion of tumor propagating cells with inherent chemoresistance does not contribute to chemotherapy resistance in murine Trp53/Rb1 deficient SCLC (49). Interesting, R273H conferred doxorubicin resistance to human colon cancer cell lines by promoting epithelial-mesenchymal transition and cancer stem cell phenotypes through gain-of-function mechanisms prompting need to test the role of cancer initiating stem cells in conferring chemoresistance in the context of Trp53 mutant expression (50).…”

Section: Discussionmentioning

confidence: 99%

TRP53 Mutants Drive Neuroendocrine Lung Cancer Through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response

Akeno

Reece

Callahan

et al. 2017

Molecular Cancer Therapeutics

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Lung cancer is the leading cause of cancer deaths with small cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53 mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common Trp53 mutations in lung cancer, combined with Rb1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC). Tumor initiation and progression occur in a remarkably consistent time frame with short latency and uniform progression to lethal metastatic disease by 7 months. R270H or R172H expression and Trp53 loss result in similar phenotypes demonstrating that Trp53 mutants promote lung carcinogenesis through loss-of-function and not gain-of-function mechanisms. Tumor responses to targeted and cytotoxic therapeutics were discordant in mice and corresponding tumor cell cultures demonstrating need to assess therapeutic response at the organismal level. Rapamycin did not have therapeutic efficacy in the mouse model despite inhibiting mTOR signaling and markedly suppressing tumor cell growth in culture. In contrast, cisplatin/etoposide treatment using a patient regimen prolonged survival with development of chemoresistance recapitulating human responses. R270H, but not R172H, expression conferred gain-of-function activity in attenuating chemotherapeutic efficacy. These data demonstrate a causative role for Trp53 mutants in development of chemoresistant lung cancer, and provide tractable preclinical models to test novel therapeutics for refractory disease.

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Identification and Targeting of Long-Term Tumor-Propagating Cells in Small Cell Lung Cancer

Cited by 76 publications

References 65 publications

264 Vasculogenic mimicry in small cell lung cancer

264 Vasculogenic mimicry in small cell lung cancer

Vasculogenic mimicry in small cell lung cancer

TRP53 Mutants Drive Neuroendocrine Lung Cancer Through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response

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