Transition Therapy: Tackling the Ecology of Tumour Phenotypic Plasticity

Phenotypic switching in cancer cells has been found to be present across tumor types. Recent studies on Glioblastoma report a remarkably common architecture of four well-defined phenotypes coexisting within high levels of intra-tumour genetic heterogeneity. Tumours grown from any cell type recapitulate the original phenotypic composition. Similar dynamics have been shown to occur in breast cancer, melanoma and likely across further cancer types. Given the adaptive potential of phenotypic switching (PHS) strategies, understanding how it drives tumour evolution and how to break down these architectures is a major priority. Here we model the ecological dynamics behind PHS. The model is able to reproduce experimental results, and specific conditions for cancer progression and clearance reveal novel features of plastic tumours and its direct consequences on therapy resistance. Following our results we discuss \textit{transition} therapy as a novel scheme to target not only combined cytotoxicity but also the rates of phenotypic switching.

Download Full-text

Transition Therapy: Tackling the Ecology of Tumor Phenotypic Plasticity

Bulletin of Mathematical Biology ◽

10.1007/s11538-021-00970-9 ◽

2021 ◽

Vol 84 (1) ◽

Author(s):

Guim Aguadé-Gorgorió ◽

Stuart Kauffman ◽

Ricard Solé

Keyword(s):

Cancer Progression ◽

Growth Dynamics ◽

Therapy Resistance ◽

Phenotypic Switching ◽

Tumor Evolution ◽

Mathematical Framework ◽

Therapeutic Success ◽

Nonlinear Growth ◽

Tumor Types ◽

Common Architecture

AbstractPhenotypic switching in cancer cells has been found to be present across tumor types. Recent studies on Glioblastoma report a remarkably common architecture of four well-defined phenotypes coexisting within high levels of intra-tumor genetic heterogeneity. Similar dynamics have been shown to occur in breast cancer and melanoma and are likely to be found across cancer types. Given the adaptive potential of phenotypic switching (PHS) strategies, understanding how it drives tumor evolution and therapy resistance is a major priority. Here we present a mathematical framework uncovering the ecological dynamics behind PHS. The model is able to reproduce experimental results, and mathematical conditions for cancer progression reveal PHS-specific features of tumors with direct consequences on therapy resistance. In particular, our model reveals a threshold for the resistant-to-sensitive phenotype transition rate, below which any cytotoxic or switch-inhibition therapy is likely to fail. The model is able to capture therapeutic success thresholds for cancers where nonlinear growth dynamics or larger PHS architectures are in place, such as glioblastoma or melanoma. By doing so, the model presents a novel set of conditions for the success of combination therapies able to target replication and phenotypic transitions at once. Following our results, we discuss transition therapy as a novel scheme to target not only combined cytotoxicity but also the rates of phenotypic switching.

Download Full-text

miR-205 in Breast Cancer: State of the Art

International Journal of Molecular Sciences ◽

10.3390/ijms22010027 ◽

2020 ◽

Vol 22 (1) ◽

pp. 27

Author(s):

Ilaria Plantamura ◽

Alessandra Cataldo ◽

Giulia Cosentino ◽

Marilena V. Iorio

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Normal Breast ◽

Response To Therapy ◽

Aberrant Expression ◽

Open Questions ◽

Tumor Tissues ◽

Breast Physiology ◽

Cancer Types

Despite its controversial roles in different cancer types, miR-205 has been mainly described as an oncosuppressive microRNA (miRNA), with some contrasting results, in breast cancer. The role of miR-205 in the occurrence or progression of breast cancer has been extensively studied since the first evidence of its aberrant expression in tumor tissues versus normal counterparts. To date, it is known that the expression of miR-205 in the different subtypes of breast cancer is decreasing from the less aggressive subtype, estrogen receptor/progesterone receptor positive breast cancer, to the more aggressive, triple negative breast cancer, influencing metastasis capability, response to therapy and patient survival. In this review, we summarize the most important discoveries that have highlighted the functional role of this miRNA in breast cancer initiation and progression, in stemness maintenance, in the tumor microenvironment, its potential role as a biomarker and its relevance in normal breast physiology—the still open questions. Finally, emerging evidence reveals the role of some lncRNAs in breast cancer progression as sponges of miR-205. Here, we also reviewed the studies in this field.

Download Full-text

Role of the NUDT Enzymes in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22052267 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2267

Author(s):

Roni H. G. Wright ◽

Miguel Beato

Keyword(s):

Breast Cancer ◽

Signaling Pathways ◽

Cancer Progression ◽

Breast Cancers ◽

Metastatic Colonization ◽

Hormone Receptor Positive ◽

Aggressive Cancer ◽

Cancer Types ◽

Metastatic Process

Despite global research efforts, breast cancer remains the leading cause of cancer death in women worldwide. The majority of these deaths are due to metastasis occurring years after the initial treatment of the primary tumor and occurs at a higher frequency in hormone receptor-positive (Estrogen and Progesterone; HR+) breast cancers. We have previously described the role of NUDT5 (Nudix-linked to moiety X-5) in HR+ breast cancer progression, specifically with regards to the growth of breast cancer stem cells (BCSCs). BCSCs are known to be the initiators of epithelial-to-mesenchyme transition (EMT), metastatic colonization, and growth. Therefore, a greater understanding of the proteins and signaling pathways involved in the metastatic process may open the door for therapeutic opportunities. In this review, we discuss the role of NUDT5 and other members of the NUDT family of enzymes in breast and other cancer types. We highlight the use of global omics data based on our recent phosphoproteomic analysis of progestin signaling pathways in breast cancer cells and how this experimental approach provides insight into novel crosstalk mechanisms for stratification and drug discovery projects aiming to treat patients with aggressive cancer.

Download Full-text

Multistability and consequent phenotypic plasticity in AMPK-Akt double negative feedback loop in cancer cells

10.1101/2020.12.21.423274 ◽

2020 ◽

Author(s):

Adithya Chedere ◽

Kishore Hari ◽

Saurav Kumar ◽

Annapoorni Rangarajan ◽

Mohit Kumar Jolly

Keyword(s):

Breast Cancer ◽

Phenotypic Plasticity ◽

Cancer Cells ◽

Cell Population ◽

Negative Feedback ◽

Feedback Loop ◽

Phenotypic Switching ◽

Negative Feedback Loop ◽

Double Negative ◽

Protein Levels

AbstractAdaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can generate majorly two phenotypes or cell states: matrix detachment-triggered pAMPKhigh/ pAktlow state, and matrix (re)attachment-triggered pAkthigh/ pAMPKlow state. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism-based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkthigh/ pAMPKlow and pAMPKhigh/pAktlow) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB-231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of TCGA breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPK-Akt feedback loop can generate multistability and drive phenotypic switching and heterogeneity in a cancer cell population.

Download Full-text

Abstract P6-04-07: Significance and therapeutic potential of PELP1-mTOR axis in breast cancer progression and therapy resistance

10.1158/0008-5472.sabcs12-p6-04-07 ◽

2012 ◽

Author(s):

VK Gonugunta ◽

V Cortez ◽

GR Sareddy ◽

SS Roy ◽

H Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Therapeutic Potential ◽

Therapy Resistance ◽

Breast Cancer Progression

Download Full-text

An H3K4me3 reader, BAP18 as an adaptor of COMPASS-like core subunits co-activates ERα action and associates with the sensitivity of antiestrogen in breast cancer

Nucleic Acids Research ◽

10.1093/nar/gkaa787 ◽

2020 ◽

Vol 48 (19) ◽

pp. 10768-10784

Author(s):

Ge Sun ◽

Chunyu Wang ◽

Shengli Wang ◽

Hongmiao Sun ◽

Kai Zeng ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Binding Sites ◽

Estrogen Receptor Alpha ◽

Target Genes ◽

Regulatory Element ◽

Therapy Resistance ◽

Ctcf Binding ◽

Promoter Regions ◽

Positive Breast Cancer

Abstract Estrogen receptor alpha (ERα) signaling pathway is essential for ERα-positive breast cancer progression and endocrine therapy resistance. Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18) has been recognized as a crucial H3K4me3 reader. However, the whole genomic occupation of BAP18 and its biological function in breast cancer is still elusive. Here, we found that higher expression of BAP18 in ERα-positive breast cancer is positively correlated with poor prognosis. ChIP-seq analysis further demonstrated that the half estrogen response elements (EREs) and the CCCTC binding factor (CTCF) binding sites are the significant enrichment sites found in estrogen-induced BAP18 binding sites. Also, we provide the evidence to demonstrate that BAP18 as a novel co-activator of ERα is required for the recruitment of COMPASS-like core subunits to the cis-regulatory element of ERα target genes in breast cancer cells. BAP18 is recruited to the promoter regions of estrogen-induced genes, accompanied with the enrichment of the lysine 4-trimethylated histone H3 tail (H3K4me3) in the presence of E2. Furthermore, BAP18 promotes cell growth and associates the sensitivity of antiestrogen in ERα-positive breast cancer. Our data suggest that BAP18 facilitates the association between ERα and COMPASS-like core subunits, which might be an essential epigenetic therapeutic target for breast cancer.

Download Full-text

Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts

Biomedicines ◽

10.3390/biomedicines9121921 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1921

Author(s):

Farhana Mollah ◽

Pegah Varamini

Keyword(s):

Breast Cancer ◽

Small Molecules ◽

Cancer Progression ◽

Triple Negative ◽

Chemotherapy Resistance ◽

Therapy Resistance ◽

Cancer Associated Fibroblasts ◽

Aggressive Form ◽

Promising Target ◽

Wide Range

Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies and results in relapse and metastasis. Breast cancer-associated fibroblasts (BCAFs) are the predominant cells that reside in the tumor microenvironment (TME) and regulate tumorigenesis, progression and metastasis, and therapy resistance. BCAFs secrete a wide range of factors, including growth factors, chemokines, and cytokines, some of which have been proved to lead to a poor prognosis and clinical outcomes. This TME component has been emerging as a promising target due to its crucial role in cancer progression and chemotherapy resistance. A number of therapeutic candidates are designed to effectively target BCAFs with a focus on their tumor-promoting properties and tumor immune response. This review explores various agents targeting BCAFs in TNBC, including small molecules, nucleic acid-based agents, antibodies, proteins, and finally, nanoparticles.

Download Full-text

SGK1 in Human Cancer: Emerging Roles and Mechanisms

Frontiers in Oncology ◽

10.3389/fonc.2020.608722 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yiwen Sang ◽

Piaoping Kong ◽

Shizhen Zhang ◽

Lingyu Zhang ◽

Ying Cao ◽

...

Keyword(s):

Cancer Progression ◽

Kinase Activity ◽

Human Cancer ◽

Therapy Resistance ◽

Cancer Cell Proliferation ◽

Serine Threonine Kinase ◽

Aberrant Expression ◽

Threonine Kinase ◽

Cancer Types

Serum and glucocorticoid-induced protein kinase 1 (SGK1) is a member of the “AGC” subfamily of protein kinases, which shares structural and functional similarities with the AKT family of kinases and displays serine/threonine kinase activity. Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer. SGK1 is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in the genesis and development of many human cancers. Abnormal expression of SGK1 has been found in tissue and may hopefully become a useful indicator of cancer progression. In addition, SGK1 acts as a prognostic factor for cancer patient survival. This review systematically summarizes and discusses the role of SGK1 as a diagnostic and prognostic biomarker of diverse cancer types; focuses on its essential roles and functions in tumorigenesis, cancer cell proliferation, apoptosis, invasion, metastasis, autophagy, metabolism, and therapy resistance and in the tumor microenvironment; and finally summarizes the current understanding of the regulatory mechanisms of SGK1 at the molecular level. Taken together, this evidence highlights the crucial role of SGK1 in tumorigenesis and cancer progression, revealing why it has emerged as a potential target for cancer therapy.

Download Full-text