Tumor Microenvironment Influences Cancer Cell Transcriptional State

The tumor microenvironment plays a critical role in modulating cancer cell migration, metabolism, and malignancy, thus, highlighting the need to develop in vitro culture systems that can recapitulate its abnormal properties. While a variety of stiffness-tunable biomaterials, reviewed here, have been developed to mimic the rigidity of the tumor extracellular matrix, culture systems that can recapitulate the broader extracellular context of the tumor microenvironment (including pH and temperature) remain comparably unexplored, partially due to the difficulty in independently tuning these parameters. Here, we investigate a self-assembled polypeptide network hydrogel as a cell culture platform and demonstrate that the culture parameters, including the substrate stiffness, extracellular pH and temperature, can be independently controlled. We then use this biomaterial as a cell culture substrate to assess the effect of stiffness, pH and temperature on Suit2 cells, a pancreatic cancer cell line, and demonstrate that these microenvironmental factors can regulate two critical transcription factors in cancer: yes-associated protein 1 (YAP) and hypoxia inducible factor (HIF-1A).

Download Full-text

In vivo optical imaging of cancer cell function and tumor microenvironment

Cancer Science ◽

10.1111/cas.13544 ◽

2018 ◽

Vol 109 (4) ◽

pp. 912-918 ◽

Cited By ~ 17

Author(s):

Takeshi Imamura ◽

Takashi Saitou ◽

Ryosuke Kawakami

Keyword(s):

Tumor Microenvironment ◽

Optical Imaging ◽

Cancer Cell ◽

Cell Function ◽

In Vivo Optical Imaging

Download Full-text

A fluorescence nanoprobe for detecting the effect of different oxygen and nutrient conditions on breast cancer cells migration and invasion

Biomaterials Science ◽

10.1039/d1bm00619c ◽

2021 ◽

Author(s):

Ping Zhou ◽

Bo Liu ◽

Mingming Luan ◽

Na Li ◽

Bo Tang

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cells ◽

Tumor Metastasis ◽

Migration And Invasion ◽

Cancer Cell Migration ◽

Fluorescence Nanoprobe

Cancer cell migration and invasion are initial steps for tumor metastasis that increases patient mortality. Tumor microenvironment is characterized by hypoxic and low nutrient-containing. Previous studies have suggested that hypoxia...

Download Full-text

Interstitial flow promotes macrophage polarization toward an M2 phenotype

Molecular Biology of the Cell ◽

10.1091/mbc.e18-03-0164 ◽

2018 ◽

Vol 29 (16) ◽

pp. 1927-1940 ◽

Cited By ~ 22

Author(s):

Ran Li ◽

Jean Carlos Serrano ◽

Hao Xing ◽

Tara A. Lee ◽

Hesham Azizgolshani ◽

...

Keyword(s):

Fluid Flow ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Cell ◽

Interstitial Fluid ◽

Macrophage Polarization ◽

Interstitial Flow ◽

Interstitial Fluid Flow ◽

M2 Polarization ◽

Tumor Tissues

Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.

Download Full-text

Abstract 3734: Cancer cell-targeted photoimmunotherapy elicits immunogenic cell death and activates the innate and adaptive immune response in the tumor microenvironment

10.1158/1538-7445.am2019-3734 ◽

2019 ◽

Author(s):

Michelle A. Hsu ◽

Stephanie M. Okamura ◽

Daniele M. Bergeron ◽

Deepak Yadav ◽

Jerry J. Fong ◽

...

Keyword(s):

Immune Response ◽

Cell Death ◽

Tumor Microenvironment ◽

Cancer Cell ◽

Adaptive Immune Response ◽

Immunogenic Cell Death ◽

Adaptive Immune

Download Full-text

322 Melanoma-intrinsic hypoxia-inducible factor-1α results in diminished T cell accumulation within the tumor microenvironment

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.322 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A347-A347

Author(s):

Emily Higgs ◽

Thomas Gajewski ◽

Jonathan Trujillo

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Cancer Cell ◽

Gene Expression Analysis ◽

Hypoxia Inducible Factor ◽

Gene Signature ◽

T Cell Response ◽

Pathway Activation ◽

Cell Accumulation ◽

The Impact

BackgroundThe hypoxia-inducible factor (HIF) system, consisting of the transcription factors HIF-1α and HIF-2α, mediates cellular adaptation to hypoxia, and can promote cancer progression, invasion, and metastasis. HIF pathway activation in the tumor microenvironment has been implicated in cancer immune evasion; however, a direct causal role for tumor cell-intrinsic HIF-1α and HIF-2α activation in mediating T cell exclusion and cancer cell resistance to immune checkpoint inhibitor therapy has not been demonstrated.MethodsWe performed gene expression analysis of melanoma tumors in the Cancer Genome Atlas (TCGA) data set to determine whether increased HIF-1α pathway activation correlated with reduced T cell-based inflammation. The magnitude of HIF-1α pathway activation across melanoma samples was determined by applying a quantitative scoring system on the expression of a melanocyte-specific hypoxia-induced, HIF-1α-target gene signature consisting of 81 genes. The Pearson correlation test was used to compare the HIF-1α activation score and our 160-gene T-cell-inflamed gene signature. To determine the impact of cancer cell-intrinsic HIF-1α or HIF-2α activation on the endogenous anti-tumor T cell response, we developed an inducible autochthonous mouse melanoma model driven by BRAFV600E expression and PTEN-deletion, with or without inducible expression of either a stabilized variant of HIF-1α or HIF-2α. These murine tumor models are being used to determine the impact of cancer cell-intrinsic HIF-1α or HIF-2α activation on tumor sensitivity to anti-PD-1/PD-L1 and anti-CTLA-4 treatment.ResultsGene expression analysis of human melanomas in the TCGA demonstrated a statistically significant inverse correlation between the HIF-1α activation score and T cell-inflammation score. Braf/PTEN murine melanomas with and without stabilized HIF-1α expression developed with comparable tumor onset and growth kinetics. Multiparameter immunofluorescence staining of melanoma tissue revealed a significant decrease in tumor-infiltrating T cells within Braf/PTEN melanoma tumors expressing stabilized HIF-1α compared to control Braf/PTEN melanomas.ConclusionsOur data demonstrate that tumor-cell intrinsic HIF-1α activation leads to diminished T cell accumulation within the tumor microenvironment, which has implications for cancer immunotherapy. The mechanism of this effect is being elucidated. These novel murine models will help elucidate the roles of cancer cell-intrinsic HIF-1α and HIF-2α activation in modulating the anti-tumor T cell response, providing mechanistic insight that will inform the evaluation of novel selective HIF inhibitors, which are showing promising anti-tumor activity in clinical trials in patients with advanced solid tumors.

Download Full-text