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26 pages, 11915 KiB

Open AccessArticle

PTP61F Mediates Cell Competition and Mitigates Tumorigenesis

by John E. La Marca, Lee F. Willoughby, Kirsten Allan, Marta Portela, Pei Kee Goh, Tony Tiganis and Helena E. Richardson

Int. J. Mol. Sci. 2021, 22(23), 12732; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312732 - 25 Nov 2021

Cited by 5 | Viewed by 2514

Abstract

Tissue homeostasis via the elimination of aberrant cells is fundamental for organism survival. Cell competition is a key homeostatic mechanism, contributing to the recognition and elimination of aberrant cells, preventing their malignant progression and the development of tumors. Here, using Drosophila as a [...] Read more.

Tissue homeostasis via the elimination of aberrant cells is fundamental for organism survival. Cell competition is a key homeostatic mechanism, contributing to the recognition and elimination of aberrant cells, preventing their malignant progression and the development of tumors. Here, using Drosophila as a model organism, we have defined a role for protein tyrosine phosphatase 61F (PTP61F) (orthologue of mammalian PTP1B and TCPTP) in the initiation and progression of epithelial cancers. We demonstrate that a Ptp61F null mutation confers cells with a competitive advantage relative to neighbouring wild-type cells, while elevating PTP61F levels has the opposite effect. Furthermore, we show that knockdown of Ptp61F affects the survival of clones with impaired cell polarity, and that this occurs through regulation of the JAK–STAT signalling pathway. Importantly, PTP61F plays a robust non-cell-autonomous role in influencing the elimination of adjacent polarity-impaired mutant cells. Moreover, in a neoplastic RAS-driven polarity-impaired tumor model, we show that PTP61F levels determine the aggressiveness of tumors, with Ptp61F knockdown or overexpression, respectively, increasing or reducing tumor size. These effects correlate with the regulation of the RAS–MAPK and JAK–STAT signalling by PTP61F. Thus, PTP61F acts as a tumor suppressor that can function in an autonomous and non-cell-autonomous manner to ensure cellular fitness and attenuate tumorigenesis. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis 2.0)

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17 pages, 6221 KiB

Open AccessArticle

Drosophila Larval Models of Invasive Tumorigenesis for In Vivo Studies on Tumour/Peripheral Host Tissue Interactions during Cancer Cachexia

by Joseph A. Hodgson, Jean-Philippe Parvy, Yachuan Yu, Marcos Vidal and Julia B. Cordero

Int. J. Mol. Sci. 2021, 22(15), 8317; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158317 - 02 Aug 2021

Cited by 7 | Viewed by 3009

Abstract

Cancer cachexia is a common deleterious paraneoplastic syndrome that represents an area of unmet clinical need, partly due to its poorly understood aetiology and complex multifactorial nature. We have interrogated multiple genetically defined larval Drosophila models of tumourigenesis against key features of human [...] Read more.

Cancer cachexia is a common deleterious paraneoplastic syndrome that represents an area of unmet clinical need, partly due to its poorly understood aetiology and complex multifactorial nature. We have interrogated multiple genetically defined larval Drosophila models of tumourigenesis against key features of human cancer cachexia. Our results indicate that cachectic tissue wasting is dependent on the genetic characteristics of the tumour and demonstrate that host malnutrition or tumour burden are not sufficient to drive wasting. We show that JAK/STAT and TNF-α/Egr signalling are elevated in cachectic muscle and promote tissue wasting. Furthermore, we introduce a dual driver system that allows independent genetic manipulation of tumour and host skeletal muscle. Overall, we present a novel Drosophila larval paradigm to study tumour/host tissue crosstalk in vivo, which may contribute to future research in cancer cachexia and impact the design of therapeutic approaches for this pathology. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis 2.0)

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15 pages, 5324 KiB

Open AccessArticle

Sensitive High-Throughput Assays for Tumour Burden Reveal the Response of a Drosophila melanogaster Model of Colorectal Cancer to Standard Chemotherapies

by Jamie Adams, Andreu Casali and Kyra Campbell

Int. J. Mol. Sci. 2021, 22(10), 5101; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105101 - 12 May 2021

Cited by 6 | Viewed by 2605

Abstract

Drosophila melanogaster (Drosophila) models of cancer are emerging as powerful tools to investigate the basic mechanisms underlying tumour progression and identify novel therapeutics. Rapid and inexpensive, it is possible to carry out genetic and drug screens at a far larger scale than in [...] Read more.

Drosophila melanogaster (Drosophila) models of cancer are emerging as powerful tools to investigate the basic mechanisms underlying tumour progression and identify novel therapeutics. Rapid and inexpensive, it is possible to carry out genetic and drug screens at a far larger scale than in vertebrate organisms. Such whole-organism-based drug screens permits assessment of drug absorption and toxicity, reducing the possibility of false positives. Activating mutations in the Wnt and Ras signalling pathways are common in many epithelial cancers, and when driven in the adult Drosophila midgut, it induces aggressive intestinal tumour-like outgrowths that recapitulate many aspects of human colorectal cancer (CRC). Here we have taken a Drosophila CRC model in which tumourous cells are marked with both GFP and luciferase reporter genes, and developed novel high-throughput assays for quantifying tumour burden. Leveraging these assays, we find that the Drosophila CRC model responds rapidly to treatment with standard CRC-drugs, opening the door to future rapid genetic and drug screens. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis 2.0)

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Review

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27 pages, 2476 KiB

Open AccessReview

Ras^V12; scrib^−/− Tumors: A Cooperative Oncogenesis Model Fueled by Tumor/Host Interactions

by Caroline Dillard, José Gerardo Teles Reis and Tor Erik Rusten

Int. J. Mol. Sci. 2021, 22(16), 8873; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168873 - 18 Aug 2021

Cited by 6 | Viewed by 4322

Abstract

The phenomenon of how oncogenes and tumor-suppressor mutations can synergize to promote tumor fitness and cancer progression can be studied in relatively simple animal model systems such as Drosophila melanogaster. Almost two decades after the landmark discovery of cooperative oncogenesis between oncogenic Ras [...] Read more.

The phenomenon of how oncogenes and tumor-suppressor mutations can synergize to promote tumor fitness and cancer progression can be studied in relatively simple animal model systems such as Drosophila melanogaster. Almost two decades after the landmark discovery of cooperative oncogenesis between oncogenic Ras^V12 and the loss of the tumor suppressor scribble in flies, this and other tumor models have provided new concepts and findings in cancer biology that has remarkable parallels and relevance to human cancer. Here we review findings using the Ras^V12; scrib^−/− tumor model and how it has contributed to our understanding of how these initial simple genetic insults cooperate within the tumor cell to set in motion the malignant transformation program leading to tumor growth through cell growth, cell survival and proliferation, dismantling of cell–cell interactions, degradation of basement membrane and spreading to other organs. Recent findings have demonstrated that cooperativity goes beyond cell intrinsic mechanisms as the tumor interacts with the immediate cells of the microenvironment, the immune system and systemic organs to eventually facilitate malignant progression. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis 2.0)

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19 pages, 27113 KiB

Open AccessReview

In Silico Logical Modelling to Uncover Cooperative Interactions in Cancer

by Gianluca Selvaggio, Claudine Chaouiya and Florence Janody

Int. J. Mol. Sci. 2021, 22(9), 4897; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094897 - 05 May 2021

Cited by 1 | Viewed by 2122

Abstract

The multistep development of cancer involves the cooperation between multiple molecular lesions, as well as complex interactions between cancer cells and the surrounding tumour microenvironment. The search for these synergistic interactions using experimental models made tremendous contributions to our understanding of oncogenesis. Yet, [...] Read more.

The multistep development of cancer involves the cooperation between multiple molecular lesions, as well as complex interactions between cancer cells and the surrounding tumour microenvironment. The search for these synergistic interactions using experimental models made tremendous contributions to our understanding of oncogenesis. Yet, these approaches remain labour-intensive and challenging. To tackle such a hurdle, an integrative, multidisciplinary effort is required. In this article, we highlight the use of logical computational models, combined with experimental validations, as an effective approach to identify cooperative mechanisms and therapeutic strategies in the context of cancer biology. In silico models overcome limitations of reductionist approaches by capturing tumour complexity and by generating powerful testable hypotheses. We review representative examples of logical models reported in the literature and their validation. We then provide further analyses of our logical model of Epithelium to Mesenchymal Transition (EMT), searching for additional cooperative interactions involving inputs from the tumour microenvironment and gain of function mutations in NOTCH. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis 2.0)

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34 pages, 3940 KiB

Open AccessReview

Modeling Neoplastic Growth in Renal Cell Carcinoma and Polycystic Kidney Disease

by Cassandra Millet-Boureima, Stephanie He, Thi Bich Uyen Le and Chiara Gamberi

Int. J. Mol. Sci. 2021, 22(8), 3918; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083918 - 10 Apr 2021

Cited by 9 | Viewed by 4275

Abstract

Renal cell carcinoma (RCC) and autosomal dominant polycystic kidney disease (ADPKD) share several characteristics, including neoplastic cell growth, kidney cysts, and limited therapeutics. As well, both exhibit impaired vasculature and compensatory VEGF activation of angiogenesis. The PI3K/AKT/mTOR and Ras/Raf/ERK pathways play important roles [...] Read more.

Renal cell carcinoma (RCC) and autosomal dominant polycystic kidney disease (ADPKD) share several characteristics, including neoplastic cell growth, kidney cysts, and limited therapeutics. As well, both exhibit impaired vasculature and compensatory VEGF activation of angiogenesis. The PI3K/AKT/mTOR and Ras/Raf/ERK pathways play important roles in regulating cystic and tumor cell proliferation and growth. Both RCC and ADPKD result in hypoxia, where HIF-α signaling is activated in response to oxygen deprivation. Primary cilia and altered cell metabolism may play a role in disease progression. Non-coding RNAs may regulate RCC carcinogenesis and ADPKD through their varied effects. Drosophila exhibits remarkable conservation of the pathways involved in RCC and ADPKD. Here, we review the progress towards understanding disease mechanisms, partially overlapping cellular and molecular dysfunctions in RCC and ADPKD and reflect on the potential for the agile Drosophila genetic model to accelerate discovery science, address unresolved mechanistic aspects of these diseases, and perform rapid pharmacological screens. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis 2.0)

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15 pages, 645 KiB

Open AccessReview

Patient-Derived Organoids as a Model for Cancer Drug Discovery

by Colin Rae, Francesco Amato and Chiara Braconi

Int. J. Mol. Sci. 2021, 22(7), 3483; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073483 - 27 Mar 2021

Cited by 22 | Viewed by 5640

Abstract

In the search for the ideal model of tumours, the use of three-dimensional in vitro models is advancing rapidly. These are intended to mimic the in vivo properties of the tumours which affect cancer development, progression and drug sensitivity, and take into account [...] Read more.

In the search for the ideal model of tumours, the use of three-dimensional in vitro models is advancing rapidly. These are intended to mimic the in vivo properties of the tumours which affect cancer development, progression and drug sensitivity, and take into account cell–cell interactions, adhesion and invasiveness. Importantly, it is hoped that successful recapitulation of the structure and function of the tissue will predict patient response, permitting the development of personalized therapy in a timely manner applicable to the clinic. Furthermore, the use of co-culture systems will allow the role of the tumour microenvironment and tissue–tissue interactions to be taken into account and should lead to more accurate predictions of tumour development and responses to drugs. In this review, the relative merits and limitations of patient-derived organoids will be discussed compared to other in vitro and ex vivo cancer models. We will focus on their use as models for drug testing and personalized therapy and how these may be improved. Developments in technology will also be considered, including the use of microfluidics, 3D bioprinting, cryopreservation and circulating tumour cell-derived organoids. These have the potential to enhance the consistency, accessibility and availability of these models. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis 2.0)

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28 pages, 1195 KiB

Open AccessReview

Co-Operativity between MYC and BCL-2 Pro-Survival Proteins in Cancer

by Walter Douglas Fairlie and Erinna F. Lee

Int. J. Mol. Sci. 2021, 22(6), 2841; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062841 - 11 Mar 2021

Cited by 18 | Viewed by 4607

Abstract

B-Cell Lymphoma 2 (BCL-2), c-MYC and related proteins are arguably amongst the most widely studied in all of biology. Every year there are thousands of papers reporting on different aspects of their biochemistry, cellular and physiological mechanisms and functions. This plethora of literature [...] Read more.

B-Cell Lymphoma 2 (BCL-2), c-MYC and related proteins are arguably amongst the most widely studied in all of biology. Every year there are thousands of papers reporting on different aspects of their biochemistry, cellular and physiological mechanisms and functions. This plethora of literature can be attributed to both proteins playing essential roles in the normal functioning of a cell, and by extension a whole organism, but also due to their central role in disease, most notably, cancer. Many cancers arise due to genetic lesions resulting in deregulation of both proteins, and indeed the development and survival of tumours is often dependent on co-operativity between these protein families. In this review we will discuss the individual roles of both proteins in cancer, describe cancers where co-operativity between them has been well-characterised and finally, some strategies to target these proteins therapeutically. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis 2.0)

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6 pages, 581 KiB

Open AccessReview

Cell Fitness: More Than Push-Ups

by Adam James Ferrari, Ronny Drapkin and Rajan Gogna

Int. J. Mol. Sci. 2021, 22(2), 518; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020518 - 07 Jan 2021

Cited by 2 | Viewed by 3378

Abstract

Cell competition (CC) is a feature that allows tumor cells to outcompete and eliminate adjacent cells that are deemed less fit. Studies of CC, first described in Drosophila melanogaster, reveal a diversity of underlying mechanisms. In this review, we will discuss three [...] Read more.

Cell competition (CC) is a feature that allows tumor cells to outcompete and eliminate adjacent cells that are deemed less fit. Studies of CC, first described in Drosophila melanogaster, reveal a diversity of underlying mechanisms. In this review, we will discuss three recent studies that expand our understanding of the molecular features governing CC. In particular, we will focus on a molecular fitness fingerprint, oncogenic pathways, and the importance of cell junction stability. A fitness fingerprint, mediated by flower (hFWE) protein isoforms, dictates that cells expressing the flower-win isoforms will outcompete adjacent flower-loss-expressing cells. The impact of the flower protein isoforms is seen in cancer progression and may have diagnostic potential. The yes-associated protein (YAP) and TAZ transcription factors, central mediators of the oncogenic Hippo pathway, elevate peritumoral fitness thereby protecting against tumor progression and provide a suppressive barrier. Similarly, COL17A1 is a key component in hemidesmosome stability, and its expression in epidermal stem cells contributes to fitness competition and aging characteristics. The contributions of these pathways to disease development and progression will help define how CC is hijacked to favor cancer growth. Understanding these features will also help frame the diagnostic and therapeutic possibilities that may place CC in the crosshairs of cancer therapeutics. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis 2.0)

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