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Tumor Microenvironment: A Key Piece in the Puzzle of Cancer...
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Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (20 February 2023) | Viewed by 39251

Special Issue Editors

Dr. Cyril Corbet

E-Mail Website
Guest Editor
Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique, UCLouvain, 1200 Brussels, Belgium
Interests: therapy resistance; cancer metabolism; tumor microenvironment; acidosis; organoids; cancer-associated fibroblasts; precision medicine
Special Issues, Collections and Topics in MDPI journals
Dr. Ivana Kurelac

E-Mail Website
Guest Editor
Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
Interests: solid cancers; mitochondria; hypoxia; cancer metabolism; tumor microenvironment; respiratory complex I

Special Issue Information

Dear Colleagues,

Cancers are now viewed as dynamic ecosystems in which subclonal populations of cancer cells and non-malignant cells within the tumor microenvironment (TME) interact cooperatively to support disease progression. Intratumoral heterogeneity has been extensively revealed in solid cancers through major advances in single-cell genomic and transcriptomic approaches. Besides genetic instability, the TME provides a strong selection pressure that shapes adaptive phenotypes in tumor cells and promotes resistance to therapy and higher metastatic potential, thereby sustaining malignant progression. Understanding the TME-related molecular mechanisms driving intratumor heterogeneity, evolution, therapy resistance, metastasis formation, and clinical relapse may allow new therapeutic avenues aiming to delay tumor progression to be identified.

For this Special Issue of Cancers, we invite authors to submit contributions that provide new insights into how TME contributes to cancer heterogeneity and tumor evolution. In particular, articles or review on new findings or concepts in the areas of metabolic plasticity, epigenetic regulation, tumor/stroma crosstalk, therapy resistance, immune escape and clinical relapse with respect to tumor evolution are of great interest. 

Dr. Ivana Kurelac
Dr. Cyril Corbet
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor microenvironment
  • tumor heterogeneity
  • drug resistance
  • epigenetics
  • metabolism
  • plasticity
  • dormancy
  • tumor evolution
  • metastasis

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Published Papers (9 papers)

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Research

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27 pages, 6383 KiB  
Article
Lung Micrometastases Display ECM Depletion and Softening While Macrometastases Are 30-Fold Stiffer and Enriched in Fibronectin
by Maria Narciso, África Martínez, Constança Júnior, Natalia Díaz-Valdivia, Anna Ulldemolins, Massimiliano Berardi, Kate Neal, Daniel Navajas, Ramon Farré, Jordi Alcaraz, Isaac Almendros and Núria Gavara
Cancers 2023, 15(8), 2404; https://doi.org/10.3390/cancers15082404 - 21 Apr 2023
Cited by 8 | Viewed by 3425
Abstract
Mechanical changes in tumors have long been linked to increased malignancy and therapy resistance and attributed to mechanical changes in the tumor extracellular matrix (ECM). However, to the best of our knowledge, there have been no mechanical studies on decellularized tumors. Here, we [...] Read more.
Mechanical changes in tumors have long been linked to increased malignancy and therapy resistance and attributed to mechanical changes in the tumor extracellular matrix (ECM). However, to the best of our knowledge, there have been no mechanical studies on decellularized tumors. Here, we studied the biochemical and mechanical progression of the tumor ECM in two models of lung metastases: lung carcinoma (CAR) and melanoma (MEL). We decellularized the metastatic lung sections, measured the micromechanics of the tumor ECM, and stained the sections for ECM proteins, proliferation, and cell death markers. The same methodology was applied to MEL mice treated with the clinically approved anti-fibrotic drug nintedanib. When compared to healthy ECM (~0.40 kPa), CAR and MEL lung macrometastases produced a highly dense and stiff ECM (1.79 ± 1.32 kPa, CAR and 6.39 ± 3.37 kPa, MEL). Fibronectin was overexpressed from the early stages (~118%) to developed macrometastases (~260%) in both models. Surprisingly, nintedanib caused a 4-fold increase in ECM-occupied tumor area (5.1 ± 1.6% to 18.6 ± 8.9%) and a 2-fold in-crease in ECM stiffness (6.39 ± 3.37 kPa to 12.35 ± 5.74 kPa). This increase in stiffness strongly correlated with an increase in necrosis, which reveals a potential link between tumor hypoxia and ECM deposition and stiffness. Our findings highlight fibronectin and tumor ECM mechanics as attractive targets in cancer therapy and support the need to identify new anti-fibrotic drugs to abrogate aberrant ECM mechanics in metastases. Full article
(This article belongs to the Special Issue Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity)
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15 pages, 2898 KiB  
Article
The KRAS-Mutant Consensus Molecular Subtype 3 Reveals an Immunosuppressive Tumor Microenvironment in Colorectal Cancer
by Pariyada Tanjak, Amphun Chaiboonchoe, Tharathorn Suwatthanarak, Onchira Acharayothin, Kullanist Thanormjit, Jantappapa Chanthercrob, Thanawat Suwatthanarak, Bundit Wannasuphaphol, Kemmapon Chumchuen, Bhoom Suktitipat, Somponnat Sampattavanich, Krittiya Korphaisarn, Ananya Pongpaibul, Naravat Poungvarin, Harald Grove, Woramin Riansuwan, Atthaphorn Trakarnsanga, Asada Methasate, Manop Pithukpakorn and Vitoon Chinswangwatanakul
Cancers 2023, 15(4), 1098; https://doi.org/10.3390/cancers15041098 - 8 Feb 2023
Cited by 14 | Viewed by 3428
Abstract
Colorectal cancers (CRC) with KRAS mutations (KRASmut) are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRASmut, focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. [...] Read more.
Colorectal cancers (CRC) with KRAS mutations (KRASmut) are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRASmut, focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of KRASmut in patients with CRC was investigated and overall survival (OS) was compared with wild-type KRAS (KRASwt). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of KRASmut and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of KRASmut in the TME regions of CMS3-classified CRC tissues. CRC patients with KRASmut were mainly enriched in CMS3. Their specific enrichments of immune gene signatures in immunosuppressive TME were associated with worse OS. Activation of TGFβ signaling by KRASmut was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of KRASmut CMS3-classified tissues suggested up-regulated genes, CD40, CTLA4, ARG1, STAT3, IDO, and CD274, that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of KRASmut in immunosuppressive TME. Future studies and clinical trials in CRC patients with KRASmut should consider these transcriptional landscapes. Full article
(This article belongs to the Special Issue Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity)
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17 pages, 4414 KiB  
Article
Identification and Characterization of Cancer-Associated Fibroblast Subpopulations in Lung Adenocarcinoma
by Daeseung Kim, Jeong Seon Kim, Inyoung Cheon, Seo Ree Kim, Sang Hoon Chun, Jae Jun Kim, Sieun Lee, Jung Sook Yoon, Soon Auck Hong, Hye Sung Won, Keunsoo Kang, Young-Ho Ahn and Yoon Ho Ko
Cancers 2022, 14(14), 3486; https://doi.org/10.3390/cancers14143486 - 18 Jul 2022
Cited by 12 | Viewed by 4324
Abstract
Cancer-associated fibroblasts (CAFs) reside within the tumor microenvironment, facilitating cancer progression and metastasis via direct and indirect interactions with cancer cells and other stromal cell types. CAFs are composed of heterogeneous subpopulations of activated fibroblasts, including myofibroblastic, inflammatory, and immunosuppressive CAFs. In this [...] Read more.
Cancer-associated fibroblasts (CAFs) reside within the tumor microenvironment, facilitating cancer progression and metastasis via direct and indirect interactions with cancer cells and other stromal cell types. CAFs are composed of heterogeneous subpopulations of activated fibroblasts, including myofibroblastic, inflammatory, and immunosuppressive CAFs. In this study, we sought to identify subpopulations of CAFs isolated from human lung adenocarcinomas and describe their transcriptomic and functional characteristics through single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatics analyses. Cell trajectory analysis of combined total and THY1 + CAFs revealed two branching points with five distinct branches. Based on Gene Ontology analysis, we denoted Branch 1 as “immunosuppressive”, Branch 2 as “neoantigen presenting”, Branch 4 as “myofibroblastic”, and Branch 5 as “proliferative” CAFs. We selected representative branch-specific markers and measured their expression levels in total and THY1 + CAFs. We also investigated the effects of these markers on CAF activity under coculture with lung cancer cells. This study describes novel subpopulations of CAFs in lung adenocarcinoma, highlighting their potential value as therapeutic targets. Full article
(This article belongs to the Special Issue Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity)
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21 pages, 10683 KiB  
Article
Single-Cell Proteomic Analysis Dissects the Complexity of Tumor Microenvironment in Muscle Invasive Bladder Cancer
by Chao Feng, Xi Wang, Yuting Tao, Yuanliang Xie, Zhiyong Lai, Zhijian Li, Jiaxin Hu, Shaomei Tang, Lixin Pan, Liangyu He, Qiuyan Wang, Tianyu Li and Zengnan Mo
Cancers 2021, 13(21), 5440; https://doi.org/10.3390/cancers13215440 - 29 Oct 2021
Cited by 11 | Viewed by 4064
Abstract
Muscle invasive bladder cancer (MIBC) is a malignancy with considerable heterogeneity. The MIBC tumor microenvironment (TME) is highly complex, comprising diverse phenotypes and spatial architectures. The complexity of the MIBC TME must be characterized to provide potential targets for precision therapy. Herein, an [...] Read more.
Muscle invasive bladder cancer (MIBC) is a malignancy with considerable heterogeneity. The MIBC tumor microenvironment (TME) is highly complex, comprising diverse phenotypes and spatial architectures. The complexity of the MIBC TME must be characterized to provide potential targets for precision therapy. Herein, an integrated combination of mass cytometry and imaging mass cytometry was used to analyze tumor cells, immune cells, and TME spatial characteristics of 44 MIBC patients. We detected tumor and immune cell clusters with abnormal phenotypes. In particular, we identified a previously overlooked cancer stem-like cell cluster (ALDH+PD-L1+ER-β−) that was strongly associated with poor prognosis. We elucidated the different spatial architectures of immune cells (excluded, infiltrated, and deserted) and tumor-associated collagens (curved, stretched, directionally distributed, and chaotic) in the MIBC TME. The present study is the first to provide in-depth insight into the complexity of the MIBC TME at the single-cell level. Our results will improve the general understanding of the heterogeneous characteristics of MIBC, potentially facilitating patient stratification and personalized therapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity)
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18 pages, 2652 KiB  
Article
EphB6 Regulates TFEB-Lysosomal Pathway and Survival of Disseminated Indolent Breast Cancer Cells
by Manuela Zangrossi, Patrizia Romani, Probir Chakravarty, Colin D.H. Ratcliffe, Steven Hooper, Martina Dori, Mattia Forcato, Silvio Bicciato, Sirio Dupont, Erik Sahai and Marco Montagner
Cancers 2021, 13(5), 1079; https://doi.org/10.3390/cancers13051079 - 3 Mar 2021
Cited by 17 | Viewed by 4932
Abstract
Late relapse of disseminated cancer cells is a common feature of breast and prostate tumors. Several intrinsic and extrinsic factors have been shown to affect quiescence and reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining the survival of [...] Read more.
Late relapse of disseminated cancer cells is a common feature of breast and prostate tumors. Several intrinsic and extrinsic factors have been shown to affect quiescence and reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining the survival of DDCCs in a foreign environment are still poorly understood. We have recently shown that crosstalk with lung epithelial cells promotes survival of DDCCs of estrogen receptor-positive (ER+) breast tumors. By using a lung organotypic system and in vivo dissemination assays, here we show that the TFEB-lysosomal axis is activated in DDCCs and that it is modulated by the pro-survival ephrin receptor EphB6. TFEB lysosomal direct targets are enriched in DDCCs in vivo and correlate with relapse in ER+ breast cancer patients. Direct coculture of DDCCs with alveolar type I-like lung epithelial cells and dissemination in the lung drive lysosomal accumulation and EphB6 induction. EphB6 contributes to survival, TFEB transcriptional activity, and lysosome formation in DDCCs in vitro and in vivo. Furthermore, signaling from EphB6 promotes the proliferation of surrounding lung parenchymal cells in vivo. Our data provide evidence that EphB6 is a key factor in the crosstalk between disseminated dormant cancer cells and the lung parenchyma and that the TFEB-lysosomal pathway plays an important role in the persistence of DDCCs. Full article
(This article belongs to the Special Issue Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity)
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Review

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40 pages, 3122 KiB  
Review
Hypoxia as a Modulator of Inflammation and Immune Response in Cancer
by Rosa A. Castillo-Rodríguez, Cristina Trejo-Solís, Alfredo Cabrera-Cano, Saúl Gómez-Manzo and Víctor Manuel Dávila-Borja
Cancers 2022, 14(9), 2291; https://doi.org/10.3390/cancers14092291 - 4 May 2022
Cited by 29 | Viewed by 5150
Abstract
A clear association between hypoxia and cancer has heretofore been established; however, it has not been completely developed. In this sense, the understanding of the tumoral microenvironment is critical to dissect the complexity of cancer, including the reduction in oxygen distribution inside the [...] Read more.
A clear association between hypoxia and cancer has heretofore been established; however, it has not been completely developed. In this sense, the understanding of the tumoral microenvironment is critical to dissect the complexity of cancer, including the reduction in oxygen distribution inside the tumoral mass, defined as tumoral hypoxia. Moreover, hypoxia not only influences the tumoral cells but also the surrounding cells, including those related to the inflammatory processes. In this review, we analyze the participation of HIF, NF-κB, and STAT signaling pathways as the main components that interconnect hypoxia and immune response and how they modulate tumoral growth. In addition, we closely examine the participation of the immune cells and how they are affected by hypoxia, the effects of the progression of cancer, and some innovative applications that take advantage of this knowledge, to suggest potential therapies. Therefore, we contribute to the understanding of the complexity of cancer to propose innovative therapeutic strategies in the future. Full article
(This article belongs to the Special Issue Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity)
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22 pages, 1733 KiB  
Review
Cytokine-Induced Senescence in the Tumor Microenvironment and Its Effects on Anti-Tumor Immune Responses
by Maximilian Rentschler, Heidi Braumüller, Priscilla S. Briquez and Thomas Wieder
Cancers 2022, 14(6), 1364; https://doi.org/10.3390/cancers14061364 - 8 Mar 2022
Cited by 18 | Viewed by 4225
Abstract
In contrast to surgical excision, chemotherapy or radiation therapy, immune checkpoint blockade therapies primarily influence cells in the tumor microenvironment, especially the tumor-associated lymphocytes and antigen-presenting cells. Besides complete remission of tumor lesions, in some patients, early tumor regression is followed by a [...] Read more.
In contrast to surgical excision, chemotherapy or radiation therapy, immune checkpoint blockade therapies primarily influence cells in the tumor microenvironment, especially the tumor-associated lymphocytes and antigen-presenting cells. Besides complete remission of tumor lesions, in some patients, early tumor regression is followed by a consolidation phase where residing tumors remain dormant. Whereas the cytotoxic mechanisms of the regression phase (i.e., apoptosis, necrosis, necroptosis, and immune cell-mediated cell death) have been extensively described, the mechanisms underlying the dormant state are still a matter of debate. Here, we propose immune-mediated induction of senescence in cancers as one important player. Senescence can be achieved by tumor-associated antigen-specific T helper 1 cells, cytokines or antibodies targeting immune checkpoints. This concept differs from cytotoxic treatment, which often targets the genetic makeup of cancer cells. The immune system’s ability to establish “defensive walls” around tumors also places the tumor microenvironment into the fight against cancer. Those “defensive walls” isolate the tumor cells instead of increasing the selective pressure. They also keep the tumor cells in a non-proliferating state, thereby correcting the derailed tissue homeostasis. In conclusion, strengthening the senescence surveillance of tumors by the immune cells of the microenvironment is a future goal to dampen this life-threatening disease. Full article
(This article belongs to the Special Issue Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity)
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18 pages, 13614 KiB  
Review
The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment
by Maria Iorio, Nikkitha Umesh Ganesh, Monica De Luise, Anna Maria Porcelli, Giuseppe Gasparre and Ivana Kurelac
Cancers 2021, 13(21), 5447; https://doi.org/10.3390/cancers13215447 - 29 Oct 2021
Cited by 5 | Viewed by 3364
Abstract
Metabolic reprogramming is a well-known hallmark of cancer, whereby the development of drugs that target cancer cell metabolism is gaining momentum. However, when establishing preclinical studies and clinical trials, it is often neglected that a tumor mass is a complex system in which [...] Read more.
Metabolic reprogramming is a well-known hallmark of cancer, whereby the development of drugs that target cancer cell metabolism is gaining momentum. However, when establishing preclinical studies and clinical trials, it is often neglected that a tumor mass is a complex system in which cancer cells coexist and interact with several types of microenvironment populations, including endothelial cells, fibroblasts and immune cells. We are just starting to understand how such populations are affected by the metabolic changes occurring in a transformed cell and little is known about the impact of metabolism-targeting drugs on the non-malignant tumor components. Here we provide a general overview of the links between cancer cell metabolism and tumor microenvironment (TME), particularly focusing on the emerging literature reporting TME-specific effects of metabolic therapies. Full article
(This article belongs to the Special Issue Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity)
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Other

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13 pages, 2111 KiB  
Brief Report
A Lung Organotypic Coculture Reveals a Role for TFEB-Lysosomal Axis in the Survival of Disseminated Dormant Cancer Cells
by Manuela Zangrossi, Probir Chakravarty, Patrizia Romani, Sirio Dupont, Steven Hooper, Erik Sahai and Marco Montagner
Cancers 2021, 13(5), 1007; https://doi.org/10.3390/cancers13051007 - 28 Feb 2021
Cited by 8 | Viewed by 3230
Abstract
(1) Background: metastatic relapse following a prolonged period of disease-free survival is a common cause of mortality for many cancer patients. Disseminated dormant cancer cells (DDCCs) lie below the radar before waking up years, or even decades, after the removal of the primary [...] Read more.
(1) Background: metastatic relapse following a prolonged period of disease-free survival is a common cause of mortality for many cancer patients. Disseminated dormant cancer cells (DDCCs) lie below the radar before waking up years, or even decades, after the removal of the primary tumor. This implies that they are able to survive in a latent state in a foreign environment for an extended period of time supported by intrinsic and extrinsic factors still to be elucidated. (2) Methods: we employed a coculture of DDCCs with lung epithelial cells together with RNA sequencing analysis to understand the overlap in gene transcription between in vivo and cocultured DDCCs. (3) Results: we found a significant overlap between the processes activated in DDCCs from lungs and in the coculture, as well as in alveolar type I cells in vivo and in coculture. We identified the transcription factor EB (TFEB)-lysosomal axis as a relevant process activated in DDCCs upon dissemination to the lung and confirmed the results in our lung coculture. Interestingly, breast cancer patients with a higher expression of TFEB targets show increased likelihood of developing relapses. (4) Conclusions: we propose that lysosomal accumulation following TFEB activation is an important feature of breast cancer DDCCs that might be exploited for future therapeutic interventions. Full article
(This article belongs to the Special Issue Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity)
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