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Small cell lung cancer (SCLC) is among the most aggressive and lethal human malignancies. Most patients with SCLC who initially respond to chemotherapy develop disease relapse. Therefore, there is a pressing need to identify novel driver mechanisms of SCLC progression to unlock treatment strategies to improve patient prognosis. SCLC cells comprise subsets of cells possessing progenitor or stem cell properties, while the underlying regulatory pathways remain elusive. Here, we identified the isoform 1 of the neurogenesis-associated protein ASPM (ASPM-I1) as a prominently upregulated stemness-associated gene during the self-renewal of SCLC cells. The expression of ASPM-I1 was found to be upregulated in SCLC cells and tissues, correlated with poor patient prognosis, and indispensable for SCLC stemness and tumorigenesis. A reporter array screening identified multiple developmental signaling pathways, including Hedgehog (Hh) and Wnt pathways, whose activity in SCLC cells depended upon ASPM-I1 expression. Mechanistically, ASPM-I1 stabilized the Hh transcriptional factor GLI1 at the protein level through a unique exon-18-encoded region by competing with the E3 ligases β-TrCP and CUL3. In parallel, ASPM-I1 sustains the transcription of the Hh pathway transmembrane regulator SMO through the WntDVL3β-catenin signaling axis. Functional studies verified that the ASPM-I1-regulated Hh and Wnt activities significantly contributed to SCLC aggressiveness in vivo. Consistently, the expression of ASPM-I1 positively correlated with GLI1 and stemness markers in SCLC tissues. This study illuminates an ASPM-I1-mediated regulatory module that drives tumor stemness and progression in SCLC, providing an exploitable diagnostic and therapeutic target.

Whilst traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. Treatment resistance and metastasis have been attributed to expansion of cancer stem-like cells (CSCs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximal tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts that induces the expression and secretion of ELR-motif-positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into CSCs and promote their invasive behaviors, leading to paradoxical tumor aggression following the therapy. By contrast, the same total accumulated dose administered as a low-dose-metronomic chemotherapy regimen largely prevented the therapy-induced stromal ELR+-chemokine paracrine signaling for CSCs, thereby substantially enhancing treatment response and extending survival of mice carrying desmoplastic cancers (Chan et al, J. Exp. Med. 2016). These studies illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy. Note: This abstract was not presented at the meeting. Citation Format: Kelvin K. Tsai, Tze-Sian Chan, Chung-Chi Hsu, Vincent C. Pai, Shenq-Shyang Huang, Valerie M. Weaver. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4763. doi:10.1158/1538-7445.AM2017-4763

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