Transcriptome Analysis of Individual Stromal Cell Populations Identifies Stroma-Tumor Crosstalk in Mouse Lung Cancer Model

Choi, Hyejin; Sheng, Jianting; Gao, Dingcheng; Li, Fuhai; Durrans, Anna; Ryu, Seongho; Lee, Sharrell B.; Narula, Navneet; Rafii, Shahin; Elemento, Olivier; Altorki, Nasser K.; Wong, Stephen T.C.; Mittal, Vivek

doi:10.1016/j.celrep.2015.01.040

Cited by 152 publications

(133 citation statements)

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“…In pancreatic cancer with its large collagen deposits, a worse prognosis was found in patients with high intratumoral stromal activity, defined by high α-SMA activity together with low collagen deposition (12). However, NSCLC appears to have a clearly different stromal composition (6,24), and the activated stroma index was not confirmed as a significant prognostic factor in the present study.…”

Section: Discussioncontrasting

confidence: 90%

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Periostin and tumor-stroma interactions in non-small cell lung cancer

et al. 2016

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Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-associated mortality globally. Interactions of the cancer cells with the tumor microenvironment are essential carcinogenic features for the majority of solid tumors, such as pancreatic cancer. The present study investigated the role of stromal activation in NSCLC and analyzed the surgical specimens of 93 patients by immunohistochemistry with regard to periostin (an extracellular matrix protein), α-smooth muscle actin (α-SMA; a marker of myofibroblasts) and cluster of differentiation 31 (CD31; a marker of endothelial cells), and the activated stroma index. There was a trend towards reduced overall survival for patients with high periostin expression (hazard ratio, 1.80; 95% confidence interval, 0.99–3.27; P=0.050). No significant correlations with overall survival were identified for α-SMA (P=0.930), CD31 (P=0.923), collagen (P=0.441) or the activated stroma index (P=0.706). In a multivariable analysis, the histological tumor subtype, tumor stage, lymph node involvement and resection status were independent prognostic factors in NSCLC, but none of the investigated immunohistochemical markers were prognostic factors. Thus, the tumor microenvironment and stroma activation did not prove to be of prognostic relevance for lung cancer, as it has been previously described for pancreatic cancer. Other markers of the microenvironment of NSCLC may be of higher prognostic value, pointing towards tumor-type specific effects.

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Section: Discussioncontrasting

confidence: 90%

“…NSCLC has distinct histopathological characteristics. Tumor-stroma interactions and the tumor microenvironment play an important role; however, the most relevant candidate markers and paracrine or autocrine crosstalk pathways appear to be different from those known for pancreatic cancer (6,24). …”

Section: Discussionmentioning

confidence: 99%

Periostin and tumor-stroma interactions in non-small cell lung cancer

et al. 2016

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“…Using an orthotopic Kras-driven NSCLC mouse model ( K-ras LSL-G12D/+ ;p53 flox/flox ), we have evaluated the differential gene expression in epithelial and intratumoral stromal cells by RNA-seq analysis [18]. Interestingly, we found that MMP14 was significantly upregulated both in intratumoral myeloid cells (CD11b + F4/80+ macrophages, Ly6C+ monocytes, Ly6G+ neutrophils) and EpCam + tumor cells (Figure 1 A and Supplementary Table 1).…”

Section: Resultsmentioning

confidence: 99%

Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor

et al. 2017

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Molecularly targeted therapies benefit approximately 15–20% of non-small cell lung cancer (NSCLC) patients carrying specific drug-sensitive mutations. Thus, there is a clinically unmet need for the identification of novel targets for drug development. Here, we performed RNA-deep sequencing to identify altered gene expression between malignant and non-malignant lung tissue. Matrix Metalloproteinase 14 (MMP14), a membrane-bound proteinase, was significantly up-regulated in the tumor epithelial cells and intratumoral myeloid compartments in both mouse and human NSCLC. Overexpression of a soluble dominant negative MMP14 (DN-MMP14) or pharmacological inhibition of MMP14 blocked invasion of lung cancer cells through a collagen I matrix in vitro and reduced tumor incidence in an orthotopic K-RasG12D/+p53−/− mouse model of lung cancer. Additionally, MMP14 activity mediated proteolytic processing and activation of Heparin-Binding EGF-like Growth Factor (HB-EGF), stimulating the EGFR signaling pathway to increase proliferation and tumor growth. This study highlights the potential for development of therapeutic strategies that target MMP14 in NSCLC with particular focus on MMP14-HB-EGF axis.

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“…The Kras -driven lung tumor microenvironment consists of diverse immune cells (34). Kras -driven 344SQ mouse tumors are metastatic and associated with fewer infiltrating CD8 + T cells in the tumor (21).…”

Section: Discussionmentioning

confidence: 99%

TUSC2 Immunogene Therapy Synergizes with Anti–PD-1 through Enhanced Proliferation and Infiltration of Natural Killer Cells in Syngeneic Kras-Mutant Mouse Lung Cancer Models

Meraz

Majidi

Cao

et al. 2018

Cancer Immunology Research

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Expression of the multikinase inhibitor encoded by tumor suppressor gene TUSC2 (also known as FUS1) is lost or decreased in non-small cell lung carcinoma (NSCLC). TUSC2 delivered systemically by nanovesicles has mediated tumor regression in clinical trials. Because of the role of TUSC2 in regulating immune cells, we assessed TUSC2 efficacy on antitumor immune responses alone and in combination with anti–PD-1 in two Kras-mutant syngeneic mouse lung cancer models. TUSC2 alone significantly reduced tumor growth and prolonged survival compared with anti–PD-1. When combined, this effect was significantly enhanced, and correlated with a pronounced increases in circulating and splenic natural killer (NK) cells and CD8+ T cells, and a decrease in Tregs, myeloid-derived suppressor cells (MDSCs), and T-cell checkpoint receptors PD-1, CTLA-4, and TIM-3. TUSC2 combined with anti–PD-1 induced tumor infiltrating more NK and CD8+ T cells and fewer MDSCs and Tregs than each agent alone, both in subcutaneous tumor and in lung metastases. NK-cell depletion abrogated the antitumor effect and Th1-mediated immune response of this combination, indicating that NK cells mediate TUSC2/anti–PD-1 synergy. Release of IL15 and IL18 cytokines and expression of the IL15Rα chain and IL18R1 were associated with NK-cell activation by TUSC2. Immune response–related gene expression in the tumor microenvironment was altered by combination treatment. These data provide a rationale for immunogene therapy combined with immune checkpoint blockade in the treatment of lung NSCLC.

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Transcriptome Analysis of Individual Stromal Cell Populations Identifies Stroma-Tumor Crosstalk in Mouse Lung Cancer Model

Cited by 152 publications

References 50 publications

Periostin and tumor-stroma interactions in non-small cell lung cancer

Periostin and tumor-stroma interactions in non-small cell lung cancer

Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor

TUSC2 Immunogene Therapy Synergizes with Anti–PD-1 through Enhanced Proliferation and Infiltration of Natural Killer Cells in Syngeneic Kras-Mutant Mouse Lung Cancer Models

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